Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient

ABSTRACT

A pharmaceutical composition for prevention and/or treatment for HIV infection or AIDS induced by the infection which comprises, as an active ingredient, a triazaspiro[5.5]undecane derivative, a quaternary ammonium salt thereof, an N-oxide thereof, or a non-toxic salt thereof, and if necessary, it may be combined with at least one member of other agents for prevention and/or treatment for HIV infection (wherein all symbols are as defined in the specification.) 
                         
The triazaspiro[5.5]undecane derivatives, the quaternary ammonium salts thereof or the N-oxides thereof, or the non-toxic salts thereof are useful in preventing and/or treating HIV infection and AIDS induced by the infection.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition forprevention and/or treatment for human immunodeficiency virus(hereinafter referred to as “HIV”) infection or acquired immunedeficiency syndrome (called AIDS) induced by the infection whichcomprises, as an active ingredient, at least one selected fromtriazaspiro[5.5]undecane derivatives, quaternary ammonium salts thereofand N-oxides thereof, and non-toxic salts thereof, and if necessary,other agents for prevention and/or treatment for HIV infection.

More particularly, it relates to a pharmaceutical composition forprevention and/or treatment for HIV infection or AIDS induced by theinfection which comprises, as an active ingredient, at least oneselected from triazaspiro[5.5]undecane derivatives represented byformula (I)

quaternary ammonium salts thereof or N-oxides thereof, or non-toxicsalts thereof, and if necessary, a protease inhibitor, a reversetranscriptase inhibitor, a fusion inhibitor and/or a chemokineregulator.

BACKGROUND ART

In the publication of International Publication No. 01/40227, it isreported that the compounds represented by formula (I) regulate theeffect of chemokine/chemokine receptor, so they are used for preventionand/or treatment of various inflammatory diseases, asthma, atopicdermatitis, urticaria, allergic diseases (allergic bronchopulmonaryaspergillosis or allergic eosinophilic gastroenteritis etc.), nephritis,nephropathy, hepatitis, arthritis, rheumatoid arthritis, psoriasis,rhinitis, conjunctivitis, ischemic reperfusion disorder, multiplesclerosis, ulcerative colitis, acute respiratory distress syndrome,cytotoxic shock, diabetes, autoimmune disease, in transplanted organrejection reactions, immunosuppression, cancer metastasis and acquiredimmune deficiency syndrome. Furthermore, in the specification, theinhibition effect on the binding of RANTES to CCR5 and the inhibitioneffect on the binding of MCP-1 to CCR2 had been found experimentally.However, the test which indicates that the compounds represented byformula (I) are used for actual HIV infection has never been described.

Furthermore, in the specification, a combination of chemokine/chemokineregulator with other drugs has never been described.

DISCLOSURE OF THE INVENTION

The present inventors have investigated, and consequently, the presentinventors have found experimentally that triazaspiro[5.5]undecanederivatives represented by formula (I), quaternary salts thereof orN-oxides thereof, or non-toxic salts thereof have effect for HIVinfection.

Furthermore, the present inventors have found that a combination oftriazaspiro[5.5]undecane derivatives represented by formula (I),quaternary salts thereof or N-oxides thereof, or non-toxic salts thereofwith at least one member of other preventive and/or treating agents forHIV infection has effect for HIV infection, too.

The present invention relates to

(1) A pharmaceutical composition for prevention and/or treatment for HIVinfection which comprises, as an active ingredient, at least onetriazaspiro[5.5]undecane derivative represented by formula (I)

[wherein R¹ is

-   (1) hydrogen,-   (2) C1-18 alkyl,-   (3) C2-18 alkenyl,-   (4) C2-18 alkynyl,-   (5) —COR⁶,-   (6) —CONR⁷R⁸,-   (7) —COOR⁹,-   (8) —SO₂R¹⁰,-   (9) —COCOOR¹¹,-   (10) —CONR¹²COR¹³,-   (11) Cyc1 or-   (12) C1-18 alkyl, C2-18 alkenyl or C2-18 alkynyl substituted by 1-5    substituents optionally selected from (a) halogen, (b) —CONR⁷R⁸, (c)    —COOR⁹, (d) —OR¹⁴, (e) —SR¹⁵, (f) —NR¹⁶R¹⁷, (g) —NR¹⁸COR¹⁹, (h)    —SO₂NR²⁰R²¹, (i) —OCOR²², (j) —NR²³SO₂R²⁴, (k) —NR²⁵COOR²⁶, (l)    —NR²⁷CONR²⁸R²⁹, (m) Cyc1, (n) keto and (o) —N(SO₂R²⁴)₂,

R⁶-R⁹, R¹¹-R²¹, R²³, R²⁵ and R²⁷-R²⁹ are each independently

-   (1) hydrogen,-   (2) C1-8 alkyl,-   (3) C2-8 alkenyl,-   (4) C2-8 alkynyl,-   (5) Cyc1 or-   (6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5    substituents optionally selected from (a) Cyc1, (b) halogen, (c)    —OR³⁰, (d) —SR³¹, (e) —NR³²R³³, (f) —COOR³⁴, (g) —CONR³⁵R³⁶, (h)    —NR³⁷COR³⁸, (i) —NR³⁹SO₂R⁴⁰ and (j) —N(SO₂R⁴⁰)₂,

R⁷ and R⁸, R²⁰ and R²¹, or R²⁸ and R²⁹, taken together, are

-   1) C2-6 alkylene,-   2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,-   3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or-   4) —(C2-6 alkylene)-NR¹⁹⁵—(C2-6 alkylene)- (wherein R¹⁹⁵ is    hydrogen, C1-8 alkyl, phenyl, or C1-8 alkyl substituted by phenyl.),

R¹⁰, R²², R²⁴ and R²⁶ are each independently

-   (1) C1-8 alkyl,-   (2) C2-8 alkenyl,-   (3) C2-8 alkynyl,-   (4) Cyc1 or-   (5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5    substituents optionally selected from (a) Cyc1, (b) halogen, (c)    —OR³⁰, (d) —SR³¹, (e) —NR³²R³³, (f) —COOR³⁴, (g) —CONR³R³⁶, (h)    —NR³⁷COR³⁸, (i) —NR³⁹SO₂R⁴⁰ and (j) —N(SO₂R⁴⁰)₂,

R³⁰—R³⁷ and R³⁹ are each independently hydrogen, C1-8 alkyl, Cyc1 orC1-8 alkyl substituted by Cyc1,

R³⁵ and R³⁶, taken together, are

-   1) C2-6 alkylene,-   2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,-   3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or-   4) —(C2-6 alkylene)-NR¹⁹⁶—(C2-6 alkylene)- (wherein R¹⁹⁶ is    hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl.),

R³⁸ and R⁴⁰ are each independently C1-8 alkyl, Cyc1 or C1-8 alkylsubstituted by Cyc1,

Cyc1 is C3-15 mono-, bi- or tri-(fused or spiro)carbocyclic ring or 3-15membered mono-, bi- or tri-(fused or spiro)cyclic hetero ring containing1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulfur atoms, whereinCyc1 may be optionally substituted by 1-5 of R⁵¹,

R⁵¹ is

-   (1) C1-8 alkyl,-   (2) C2-8 alkenyl,-   (3) C2-8 alkynyl,-   (4) halogen,-   (5) nitro,-   (6) trifluoromethyl,-   (7) trifluoromethoxy,-   (8) nitrile,-   (9) keto,-   (10) Cyc2,-   (11) —OR⁵²,-   (12) —SR⁵³,-   (13) —NR⁵⁴R⁵⁵,-   (14) —COOR⁵⁶,-   (15) —CONR⁵⁷R⁵⁸,-   (16) —NR⁵⁹COR⁶⁰,-   (17) —SO₂NR⁶¹R⁶²,-   (18) —OCOR⁶³,-   (19) —NR⁶⁴SO₂R⁶⁵,-   (20) —NR⁶⁶COOR⁶⁷,-   (21) —NR⁶⁸CONR⁶⁹R⁷⁰,-   (22) —B(OR⁷¹)₂,-   (23) —SO₂R⁷²,-   (24) —N(SO₂R⁷²)₂,-   (25) —S(O)R⁷² or-   (26) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5    substituents optionally selected from (a) halogen, (b) Cyc2, (c)    —OR⁵², (d) —SR⁵³, (e) —NR⁵⁴R⁵⁵, (f) —COOR⁵⁶, (g) —CONR⁵⁷R⁵⁸, (h)    —NR⁵⁹COR⁶⁰, (i) —SO₂NR⁶¹R⁶², (j) —OCOR⁶³, (k) —NR⁶⁴SO₂R⁶⁵, (l)    —NR⁶⁶COOR⁶⁷, (m) —NR⁶⁸CONR⁶⁹R⁷⁰, (n) —B(OR⁷¹)₂, (o) —SO₂R⁷², (p)    —N(SO₂R⁷²)₂, (q) —S(O)R⁷² and (r) keto,

R⁵²-R⁶², R⁶⁴, R⁶⁶ and R⁶⁸-R⁷¹ are each independently

-   1) hydrogen,-   2) C1-8 alkyl,-   3) C2-8 alkenyl,-   4) C2-8 alkynyl,-   5) Cyc2 or-   6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc2,    —OR⁷³, —COOR⁷⁴ or —NR⁷⁵R⁷⁶,

R⁵⁷ and R⁵⁸, R⁶¹ and R⁶², or R⁶⁹ and R⁷⁰, taken together, are

-   1) C2-6 alkylene,-   2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,-   3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or-   4) —(C2-6 alkylene)-NR¹⁹⁷—(C2-6 alkylene)- (wherein R¹⁹⁷ is    hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl.),

R⁶³, R⁶⁵, R⁶⁷ and R⁷² are each independently

-   1) C1-8 alkyl,-   2) C2-8 alkenyl,-   3) C2-8 alkynyl,-   4) Cyc2 or-   5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc2,    —OR⁷³, —COOR⁷⁴ or —NR⁷⁵R⁷⁶,

R⁷³-R⁷⁶ are each independently hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkylsubstituted by Cyc2,

Cyc2 has the same meaning as Cyc1, wherein Cyc2 may be optionallysubstituted by 1-5 of R⁷⁷,

R⁷⁷ is

-   1) C1-8 alkyl,-   2) halogen,-   3) nitro,-   4) trifluoromethyl,-   5) trifluoromethoxy,-   6) nitrile,-   7) —OR⁷⁸,-   8) —NR⁷⁹R⁸⁰,-   9) —COOR⁸¹,-   10) —SR⁸²,-   11) —CONR⁸³R⁸⁴,-   12) C2-8 alkenyl,-   13) C2-8 alkynyl,-   14) keto,-   15) Cyc6,-   16) —NR¹⁶¹COR¹⁶²,-   17) —SO₂NR¹⁶³R¹⁶⁴,-   18) —OCOR¹⁶⁵,-   19) —NR¹⁶⁶SO₂R¹⁶⁷,-   20) —NR¹⁶⁸COOR¹⁶⁹,-   21) —NR¹⁷⁰CONR¹⁷¹R¹⁷²,-   22) —SO₂R¹⁷³,-   23) —N(SO₂R¹⁶⁷)₂,-   24) —S(O)R¹⁷³ or-   25) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5    substituents optionally selected from (a) halogen, (b) —OR⁷⁸, (c)    —NR⁷⁹R⁸⁰, (d) —COOR⁸¹, (e) —SR⁸², (f) —CONR⁸³R⁸⁴, (g) keto, (h)    Cyc6, (i) —NR¹⁶¹COR¹⁶², (j) —SO₂NR¹⁶³R¹⁶⁴, (k) —OCOR¹⁶⁵, (l)    —NR¹⁶⁶SO₂R¹⁶⁷, (m) —NR¹⁶⁸COOR¹⁶⁹, (n) —NR¹⁷⁰CONR¹⁷¹R¹⁷², (o)    —SO₂R¹⁷³, (p) —N(SO₂R¹⁶⁷)₂ and (q) —S(O)R¹⁷³,

R⁷⁸-R⁸⁴, R¹⁶¹-R¹⁶⁴, R¹⁶⁶, R¹⁶⁸ and R¹⁷⁰-R¹⁷² are each independently, (a)hydrogen, (b) C1-8 alkyl, (c) C2-8 alkenyl, (d) C2-8 alkynyl, (e) Cyc6,(f) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc6,—OR¹⁷⁴, —COOR¹⁷⁵, —NR¹⁷⁶R¹⁷⁷ or —CONR¹⁷⁸R¹⁷⁹,

R⁸³ and R⁸⁴, R¹⁶³ and R⁶⁴, or R¹⁷¹ and R¹⁷², taken together, are

-   1) C2-6 alkylene,-   2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,-   3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or-   4) —(C2-6 alkylene)-NR¹⁹⁸—(C2-6 alkylene)- (wherein R¹⁹⁸ is    hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl.),

R¹⁶⁵, R¹⁶⁷, R¹⁶⁹ and R¹⁷³ are each independently (a) C1-8 alkyl, (b)C2-8 alkenyl, (c) C2-8 alkynyl, (d) Cyc6 or (e) C1-8 alkyl, C2-8 alkenylor C2-8 alkynyl substituted by Cyc6, —OR¹⁷⁴, —COOR¹⁷⁵, —NR¹⁷⁶R¹⁷⁷ or—CONR¹⁷⁸R¹⁷⁹,

R¹⁷⁴-R¹⁷⁷ are each independently

-   1) hydrogen,-   2) C1-8 alkyl,-   3) Cyc6 or-   4) C1-8 alkyl substituted by Cyc6,

R¹⁷⁸ and R¹⁷⁹, taken together, are

-   1) C2-6 alkylene,-   2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,-   3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or-   4) —(C2-6 alkylene)-NR¹⁹⁹—(C2-6 alkylene)- (wherein R¹⁹⁹ is    hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl.),

Cyc6 is C3-8 mono-carbocyclic ring or 3-8 membered mono-cyclic heteroring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfuratoms, wherein Cyc6 may be optionally substituted by 1-5 of R¹⁸⁰,

R¹⁸⁰ is

-   (1) C1-8 alkyl,-   (2) halogen,-   (3) nitro,-   (4) trifluoromethyl,-   (5) trifluoromethoxy,-   (6) nitrile,-   (7) —OR¹⁸¹,-   (8) —NR¹⁸²R¹⁸³,-   (9) —COOR¹⁸⁴,-   (10) —SR¹⁸⁵ or-   (11) —CONR¹⁸⁶R¹⁸⁷,

R¹⁸¹-R¹⁸⁷ are each independently

-   1) hydrogen,-   2) C1-8 alkyl,-   3) phenyl or-   4) C1-8 alkyl substituted by phenyl,

R¹⁸² and R¹⁸³, or R¹⁸⁵ and R¹⁸⁷, taken together, are

-   1) C2-6 alkylene,-   2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,-   3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or-   4) —(C2-6 alkylene)-NR²⁰⁰—(C2-6 alkylene)- (wherein R²⁰⁰ is    hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted by phenyl.),

R² is

-   (1) hydrogen,-   (2) C1-8 alkyl,-   (3) C2-8 alkenyl,-   (4) C2-8 alkynyl,-   (5) —OR⁹⁰,-   (6) Cyc3 or-   (7) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5    substituents optionally selected from (a) halogen, (b) —OR⁹⁰, (c)    —SR⁹¹, (d) —NR⁹²R⁹³, (e) —COOR⁹⁴, (f) —CONR⁹⁵R⁹⁶, (g)    —NR⁹⁷COR⁹⁸, (h) —SO₂NR⁹⁹R¹⁰⁰, (i) —OCOR¹⁰¹, (j) —NR¹⁰²SO₂R¹⁰³, (k)    —NR¹⁰⁴COOR¹⁰⁵, (l) —NR¹⁰⁶CONR¹⁰⁷R¹⁰⁸, (m) Cyc3, (n) keto and (o)    —N(SO₂R¹⁰³)₂,

R⁹⁰-R¹⁰⁰, R¹⁰², R¹⁰⁴ and R¹⁰⁶-R¹⁰⁸ are each independently

-   1) hydrogen,-   2) C1-8 alkyl,-   3) C2-8 alkenyl,-   4) C2-8 alkynyl,-   5) Cyc3 or-   6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc3,

R⁹⁵ and R⁹⁶, R⁹⁹ and R¹⁰⁰, or R¹⁰⁷ and R¹⁰⁸, taken together, are

-   1) C2-6 alkylene,-   2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,-   3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or-   4) —(C2-6 alkylene)-NR²⁰¹—(C2-6 alkylene)-,

R²⁰¹ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted byphenyl,

R¹⁰¹, R¹⁰³ and R¹⁰⁵ are each independently

-   1) C1-8 alkyl,-   2) C2-8 alkenyl,-   3) C2-8 alkynyl or-   4) Cyc3, or C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by    Cyc3,

Cyc3 has the same meaning as Cyc1, wherein Cyc3 may be optionallysubstituted by 1-5 of R¹⁰⁹,

R¹⁰⁹ has the same meaning as R⁵¹,

R³ and R⁴ are each independently

-   (1) hydrogen,-   (2) C1-8 alkyl,-   (3) C2-8 alkenyl,-   (4) C2-8 alkynyl,-   (5) —COOR¹²⁰,-   (6) —CONR¹²¹R¹²²,-   (7) Cyc4 or-   (8) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5    substituents selected from (a) halogen, (b) nitrile, (c) Cyc4, (d)    —COOR¹²⁰, (e) —CONR¹²¹R¹²², (f) —OR¹²³, (g) —SR¹²⁴, (h)    —NR¹²⁵R¹²⁶, (i) —NR¹²⁷COR¹²⁸, (j) —SO₂NR¹²⁹R¹³⁰, (k) —OCOR¹³¹, (l)    —NR¹³²SO₂R¹³³, (m) —NR¹³⁴COOR¹³⁵, (n) —NR¹³⁶CONR¹³⁷R¹³⁸, (o)    —S—SR¹³⁹, (p) —NHC(═NH)NHR¹⁴⁰, (q) keto, (r) —NR¹⁴⁵CONR¹⁴⁶COR¹⁴⁷    and (s) —N(SO₂R¹³³)₂,

R¹²⁰-R¹³⁰, R¹³², R¹³⁴, R¹³⁶-R¹³⁸, R¹⁴⁵ and R¹⁴⁶ are each independently

-   1) hydrogen,-   2) C1-8 alkyl,-   3) C2-8 alkenyl,-   4) C2-8 alkynyl,-   5) Cyc4 or-   6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4,    halogen, —OR¹⁴⁸, —SR¹⁴⁹, —COOR¹⁵⁰ or —NHCOR¹⁴¹,

R¹²¹ and R¹²², R¹²⁹ and R¹³⁰, or R¹³⁷ and R¹³⁸, taken together, are

-   1) C2-6 alkylene,-   2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,-   3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or-   4) —(C2-6 alkylene)-NR²⁰²—(C2-6 alkylene)- (wherein R²⁰² is    hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted by phenyl.),

R¹³¹, R¹³³, R¹³⁵, R¹³⁹ and R¹⁴⁷ are each independently

-   1) C1-8 alkyl,-   2) C2-8 alkenyl,-   3) C2-8 alkynyl,-   4) Cyc4 or-   5) C1-₈ alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4,    halogen, —OR¹⁴⁸, —SR¹⁴⁹, —COOR¹⁵⁰ or —NHCOR¹⁴¹,

R¹⁴⁰ is hydrogen, —COOR¹⁴² or —SO₂R¹⁴³,

R¹⁴¹-R¹⁴³ are each independently

-   1) C1-8 alkyl,-   2) C2-8 alkenyl,-   3) C2-8 alkynyl,-   4) Cyc4 or-   5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4,

R¹⁴⁸-R¹⁵⁰ are each independently

-   1) hydrogen,-   2) C1-8 alkyl,-   3) C2-8 alkenyl,-   4) C2-8 alkynyl,-   5) Cyc4 or-   6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4,

Cyc4 has the same meaning as Cyc1, wherein Cyc4 may be optionallysubstituted by 1-5 of R¹⁴⁴, and R¹⁴⁴ has the same meaning as R⁵¹,

R³ and R⁴, taken together, are

(wherein R¹⁹⁰ and R¹⁹¹ are each independently the same meaning as R³ orR⁴.),

R⁵ is

-   (1) hydrogen,-   (2) C1-8 alkyl,-   (3) Cyc5 or-   (4) C1-8 alkyl substituted by Cyc5.

(wherein Cyc5 has the same meaning as Cyc1, and Cyc5 may be optionallysubstituted by 1-5 of R¹⁶⁰,

R¹⁶⁰ has the same meaning as R⁵¹.)], a quaternary ammonium salt thereof,an N-oxide thereof, or a non-toxic salt thereof,

(2) A pharmaceutical composition for prevention and/or treatment forAIDS, which comprises, as an active ingredient, at least onetriazaspiro[5.5]undecane derivative represented by formula (I) accordingto above 1, a quaternary ammonium salt thereof, an N-oxide thereof, or anon-toxic salt thereof,

(3) A pharmaceutical composition for prevention and/or treatment for HIVinfection acquiring multidrug resistance, which comprises, as an activeingredient, at least one triazaspiro[5.5]undecane derivative representedby formula (I) according to above 1, a quaternary ammonium salt thereof,an N-oxide thereof, or a non-toxic salt thereof,

(4) A pharmaceutical composition for prevention and/or treatment for HIVinfection, which comprises a combination of at least onetriazaspiro[5.5]undecane derivative represented by formula (I) accordingto above 1, a quaternary ammonium salt thereof, an N-oxide thereof, or anon-toxic salt thereof with at least one other preventive and/ortreating agent for HIV infection,

(5) A pharmaceutical composition for prevention and/or treatment forAIDS, which comprises a combination of at least onetriazaspiro[5.5]undecane derivative represented by formula (I) accordingto above 1, a quaternary ammonium salt thereof, an N-oxide thereof, or anon-toxic salt thereof with at least one other preventive and/ortreating agent for HIV infection,

(6) A pharmaceutical composition for prevention and/or treatment for HIVinfection acquiring multidrug resistance, which comprises a combinationof at least one triazaspiro[5.5]undecane derivative represented byformula (I) according to above 1, a quaternary ammonium salt thereof, anN-oxide thereof, or a non-toxic salt thereof with at least one otherpreventive and/or treating agents for HIV infection,

(7) The pharmaceutical composition according to any one of above 4, 5and 6, wherein the other preventive and/or treating agent for HIVinfection is a protease inhibitor, a reverse transcriptase inhibitor, afusion inhibitor and/or a chemokine regulator,

(8) A pharmaceutical composition for prevention and/or treatment for HIVinfection having more enhanced treating effect than a singlepreparation, which comprises a combination of at least onetriazaspiro[5.5]undecane derivative represented by formula (I) accordingto above 1, a quaternary ammonium salt thereof, an N-oxide thereof, or anon-toxic salt thereof with a drug which does not inhibit HIV infection.

DISCLOSURE OF THE INVENTION

In the present invention, C1-18 alkyl means methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl orisomeric groups thereof.

C2-18 alkenyl means C2-18 alkylene optionally having 1-9 double bond(s)(preferably 1-4 double bond(s)), concretely, vinyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl,dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl,heptadecenyl, octadecenyl, butadienyl, pentadienyl, hexadienyl,heptadienyl, octadienyl, nonadienyl, decadienyl, undecadienyl,dodecadienyl, tridecadienyl, tetradecadienyl, pentadecadienyl,hexadecadienyl, heptadecadienyl, octadecadienyl, hexatrienyl,heptatrienyl, octatrienyl, nonatrienyl, decatrienyl, undecatrienyl,dodecatrienyl, tridecatrienyl, tetradecatrienyl, pentadecatrienyl,hexadecatrienyl, heptadecatrienyl, octadecatrienyl or isomeric groupsthereof.

C2-18 alkynyl means C2-18 alkylene optionally having 1-9 triple bond(s)(preferably 1-4 triple bond(s)), concretely, ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl,dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl,heptadecynyl, octadecynyl, butadiynyl, pentadiynyl, hexadiynyl,heptadiynyl, octadiynyl, nonadiynyl, decadiynyl, undecadiynyl,dodecadiynyl, tridecadiynyl, tetradecadiynyl, pentadecadiynyl,hexadecadiynyl, heptadecadiynyl, octadecadiynyl, hexatriynyl,heptatriynyl, octatriynyl, nonatriynyl, decatriynyl, undecatriynyl,dodecatriynyl, tridecatriynyl, tetradecatriynyl, pentadecatriynyl,hexadecatriynyl, heptadecatriynyl, octadecatriynyl or isomeric groupsthereof.

Halogen is chlorine, bromine, fluorine or iodine.

C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl or isomeric groups thereof.

C2-8 alkenyl means C2-8 alkylene optionally having 1-4 double bond(s),concretely, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl,octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl,hexatrienyl, heptatrienyl, octatrienyl or isomeric groups thereof.

C2-8 alkynyl means C2-8 alkylene optionally having 1-4 triple bond(s),concretely, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl,hexatriynyl, heptatriynyl, octatriynyl or isomeric groups thereof.

C2-6 alkylene means methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene or isomeric groups thereof.

C3-15 mono-, bi- or tri-(fused or spiro)carbocyclic ring meansconcretely, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene,cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene,cyclooctadiene, benzene, indene, naphthalene, indan,tetrahydronaphthalene, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane,bicyclo[4.4.0]decane, spiro[4.4]nonane, spiro[4.5]decane,spiro[5.5]undecane, bicyclo[3.1.1]heptane, bicyclo[3.3.1]hept-2-ene,fluorene or anthracene etc.

3-15 membered mono-, bi- or tri-(fused or spiro)cyclic hetero ringcontaining 1-4 nitrogen atom(s), 1-3 oxygen atom(s) and/or 1-3 sulfuratom(s) means 3-15 membered mono-, bi- or tri-(fused or spiro)cyclichetero aryl containing 1-4 nitrogen atom(s), 1-3 oxygen atom(s) and/or1-3 sulfur atom(s), and partially or fully saturated one.

3-15 membered mono-, bi- or tri-(fused or spiro)cyclic hetero arylcontaining 1-4 nitrogen atom(s), 1-3 oxygen atom(s) and/or 1-3 sulfuratom(s) is pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran,oxepine, thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzimidazole, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, acridine, dibenzofuran or dibenzothiopheneetc.

In above 3-15 membered mono-, bi- or tri-(fused or spiro)cyclic heteroring containing 1-4 nitrogen atom(s), 1-3 oxygen atom(s) and/or 1-3sulfur atom(s), partially or fully saturated one is pyrroline,pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiain (dihydrothiopyran), tetrahydrothiain(tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole,dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole,tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole,dihydrooxadiazole, tetrahydrooxadiazole, dihydrothiodiazole,tetrahydrothiodiazole, tetrahydrooxadiazine, tetrahydrothiadiazine,tetrahydrooxazepine, tetrahydrooxadiazepine, perhydrooxazepine,perhydrooxadiazepine, tetrahydrothiazepine, tetrahydrothiadiazepine,perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine,dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane,benzodioxalane, benzodioxane, benzodithiolane, benzodithiane,2,4,6-trioxaspiro[bicyclo[3.3.0]octane-3,1′-cyclohexane],1,3-dioxolano[4,5-g]chromene or 2-oxabicyclo[2.2.1]heptane etc.

C3-8 mono-carbocyclic ring is concretely, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene,cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene or benzene etc.

3-8 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s),1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) means 3-8 memberedmono-cyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atomand/or 1-2 sulfur atom(s) and partially or fully saturated one.

3-8 membered mono-cyclic hetero aryl containing 1-4 nitrogen atom(s),1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) is pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiain(thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole,furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine,thiadiazole, thiazine, thiadiazine, thiazepine or thiadiazepine etc.

In above 3-8 membered mono-cyclic hetero ring containing 1-4 nitrogenatom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s), partially orfully saturated one is pyrroline, pyrrolidine, imidazoline,imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiain (dihydrothiopyran), tetrahydrothiain(tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole,dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole,tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole,dihydrooxadiazole, tetrahydrooxadiazole, dihydrothiodiazole,tetrahydrothiodiazole, tetrahydrooxadiazine, tetrahydrothiadiazine,tetrahydrooxazepine, tetrahydrooxadiazepine, perhydrooxazepine,perhydrooxadiazepine, tetrahydrothiazepine, tetrahydrothiadiazepine,perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine,dioxolane, dioxane, dithiolane or dithiane etc.

In the present invention, each group represented by R¹, R², R³, R⁴ or R⁵is all preferable.

Preferred R¹ is C1-18 alkyl substituted by Cyc 1, C2-18 alkenylsubstituted by Cyc 1 or C2-18 alkynyl substituted by Cyc 1, and morepreferred R¹ is C1-6 alkyl substituted by Cyc 1.

Preferred Cyc 1 is C3-10 mono- or bi-(fused or spiro)carbocyclic ring or3-10 membered mono- or bi-(fused or spiro)cyclic hetero ring containing1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s), andmore preferred Cyc 1 is C5-7 mono-carbocyclic aryl or 5-10 memberedmono-cyclic hetero ring containing 1-4 nitrogen atom(s), 2 oxygen atomsand/or 1 sulfur atom.

Preferred Cyc 1 concretely is benzene, pyrazole, imidazole, furan,thiophene, benzodioxane, thiazole or quinoline.

Preferred R⁵¹ which is a substituent of Cyc 1 is Cyc 2, —OR⁵², —SR⁵³ or—NR⁵⁴R⁵⁵. Preferred R⁵², R⁵³, R⁵⁴ and R⁵⁵ are C1-8 alkyl or Cyc 2, andmore preferred R⁵², R⁵³, R⁵⁴ and R⁵⁵ are methyl, ethyl, propyl orphenyl.

Preferred Cyc 2 is C5-7 mono-carbocyclic aryl or 5-7 memberedmono-cyclic hetero aryl containing 1-4 nitrogen atom(s), 1 oxygen atomand/or 1 sulfur atom, and more preferred Cyc 2 is benzene.

Preferred R⁷⁷ which is a substituent of Cyc 2 is —CONR⁸³R⁸⁴,—NR¹⁶¹COR¹⁶², —SO₂NR¹⁶³R¹⁶⁴, —NR¹⁶⁶SO₂R¹⁶⁷, C1-8 alkyl substituted by—CONR⁸³R⁸⁴, C1-8 alkyl substituted by —NR¹⁶¹COR¹⁶², C1-8 alkylsubstituted by —SO₂NR¹⁶³R¹⁶⁴ or C1-8 alkyl substituted by —NR¹⁶⁶SO₂R¹⁶⁷.Preferred R⁸³, R⁸⁴, R¹⁶¹, R¹⁶², R¹⁶³, R¹⁶⁴, R¹⁶⁶ and R¹⁶⁷ are C1-8alkyl, Cyc6, C1-8 alkyl substituted by —NR¹⁷⁶R¹⁷⁷, and more preferredR⁸³, R⁸⁴, R¹⁶¹, R¹⁶², R¹⁶³, R¹⁶⁴, R¹⁶⁶ and R¹⁶⁷ are methyl, ethyl,propyl, phenyl or dimethylaminoethyl etc.

Most preferred R¹ is phenylethyl, phenylpropyl, phenylbutyl,phenylpentyl, phenylhexyl, 4-methoxyphenylmethyl,4-propyloxyphenylmethyl, 4-phenyloxyphenylmethyl,3,5-dimethyl-1-phenylpyrazol-4-ylmethyl, 2-phenylimidazol-4-ylmethyl,5-ethylfuran-2-ylmethyl, 5-ethylthiophen-2-ylmethyl,3-chloro-5-methyl-1-phenylpyrazol-4-ylmethyl,1,4-benzodioxan-6-ylmethyl,4-(4-methylsulfonylaminophenyloxy)phenylmethyl,4-(4-(2-dimethylaminoethylsulfonylamino)phenyloxy)phenylmethyl,4-(4-dimethylaminosulfonylphenyloxy)phenylmethyl,4-(4-methylcarbonylaminophenyloxy)phenylmethyl,4-(4-(2-dimethylaminoethylcarbonylamino)phenyloxy)phenylmethyl or4-(4-dimethylaminocarbonylphenyloxy)phenylmethyl etc.

Preferred R² is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylsubstituted by Cyc 3. Most preferred R² is C1-4 alkyl, C2-4 alkenyl orC2-4 alkynyl.

Most preferred R² is ethyl, propyl, butyl, 2-propenyl, 2-butenyl,2-propynyl, phenylmethyl, thiophen-2-ylmethyl or 2-butynyl etc.

Preferred R³ or R⁴ is hydrogen, C1-8 alkyl, C1-8 alkyl substituted byCyc4, C1-8alkyl substituted by —OR¹²³, C1-8 alkyl substituted by Cyc4and —OR¹²³, C1-8 alkyl substituted by —NR¹²⁷COR¹²⁸, C1-8 alkylsubstituted by —NR¹³²SO₂R¹³³, C1-8 alkyl substituted by —NR¹³⁴COOR¹³⁵ orC1-8 alkyl substituted by —NR¹³⁶CONR¹³⁷R¹³⁸. Most preferred R³ or R⁴ isC1-4 alkyl, C1-4 alkyl substituted by Cyc4, C1-4 alkyl substituted by—OR¹²³, C1-4 alkyl substituted by Cyc4 and —OR¹²³, C1-4 alkylsubstituted by —NR¹²⁷COR¹²⁸, C1-4 alkyl substituted by —NR¹³²SO₂R¹³³,C1-4 alkyl substituted by —NR¹³⁴COOR¹³⁵ or C1-4 alkyl substituted by—NR¹³⁶CONR¹³⁷R¹³⁸.

Preferred Cyc 4 is benzene or cyclohexane.

Preferred R¹²³ is hydrogen, C1-4 alkyl, Cyc 4 or C1-4 alkyl substitutedby Cyc 4, and more preferred R¹²³ is hydrogen, methyl, ethyl, phenyl orphenylmethyl.

Preferred R¹²⁷, R¹³², R¹³⁴, R¹³⁶ and R¹³⁸ are hydrogen or methyl.

Preferred R¹²⁸, R¹³³, R¹³⁵ and R¹³⁷ are Cyc 4 or C1-4 alkyl substitutedby Cyc 4, and more preferred R¹²⁸, R¹³³, R¹³⁵ and R¹³⁷ are phenyl,phenylmethyl or phenylethyl.

Preferred R¹⁴⁴ which is a substitute of Cyc 4 is C1-4 alkyl, halogen,phenyl or phenyloxy, and more preferred R¹⁴⁴ is methyl, fluorine,chlorine, phenyl or phenyloxy.

Most preferred R³ or R⁴ is propyl, 1-methylpropyl, 2-methylpropyl,cyclohexylmethyl, 1-hydroxy-2-methylpropyl,1-hydroxy-1-cyclohexylmethyl, 3-(cyclopentylethylcarbonyl)aminobutyl,3-(benzyloxycarbonyl)aminopropyl, 3-(phenylcarbonyl)aminobutyl,3-(phenylmethylcarbonyl)aminobutyl, 3-(phenylethylcarbonyl)aminobutyl,3-(phenylethenylcarbonyl)aminobutyl,3-(4-phenylphenylcarbonyl)aminobutyl,3-(4-phenyloxyphenylaminocarbonyl)aminobutyl,3-(4-chlorophenylaminocarbonyl)aminobutyl,3-(4-fluorophenylaminocarbonyl)aminobutyl,3-(phenylmethylaminocarbonyl)aminobutyl,3-(4-trifluoromethylsulfonyl)aminobutyl,4-(cyclopentylethylcarbonyl)aminobutyl, 4-(benzyloxycarbonyl)aminobutyl,4-(phenylcarbonyl)aminobutyl, 4-(phenylmethylcarbonyl)aminobutyl,4-(phenylethylcarbonyl)aminobutyl, 4-(phenylethenylcarbonyl)aminobutyl,4-(4-phenylphenylcarbonyl)aminobutyl,4-(4-phenyloxyphenylaminocarbonyl)aminobutyl,4-(4-chlorophenylaminocarbonyl)aminobutyl,4-(4-fluorophenylaminocarbonyl)aminobutyl,4-(phenylmethylaminocarbonyl)aminobutyl or4-(4-trifluoromethylsulfonyl)aminobutyl.

Preferred R⁵ is hydrogen or methyl.

In the compounds of the present invention of formula (I), the compoundrepresented by formula (Ia)

(wherein R² is C1-8 alkyl,

R³ is C1-8 alkyl or C3-7 cycloalkyl(C1-4)alkyl,

R⁵ is hydrogen or C1-8 alkyl,

A is a bond or C1-10 alkylene,

D ring is C3-10 mono- or bi-(fused or spiro)carbocyclic ring or 3-10membered mono- or bi-(fused or spiro)cyclic hetero ring,

m is 0 or an integer of 1-4,

R³⁰⁰ is C1-4 alkyl, C1-4 alkoxy, phenyl, phenoxy or benzyloxy.)

is preferable.

Preferred C3-10 carbocyclic ring represented by D ring is C3-10 mono- orbi-carbocyclic ring, and more preferred C3-10 carbocyclic ring is C3-7mono-carbocyclic ring or C8-10 bi-carbocyclic ring.

Preferred 3-10 membered cyclic hetero ring represented by D ring is 3-10membered mono- or bi-cyclic hetero aryl containing 1-4 nitrogen atom(s),1-2 oxygen atom(s) and/or 1 sulfur atom, or partially or fully saturatedone. More preferred 3-10 membered cyclic hetero ring is 5-7 memberedmono- or 8-10 membered bi-cyclic hetero aryl containing 1-4 nitrogenatom(s), 1-2 oxygen atom(s) and/or 1 sulfur atom, or partially or fullysaturated one.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkoxy and alkylene groups includestraight or branched ones. In addition, isomers on double bond, ring,fused ring (E-, Z-, cis-, trans-isomer), isomers generated fromasymmetric carbon atom(s) (R-, S-, α-, β-isomer, enantiomer,diastereomer), optically active isomer (D-, L-, d-, I-isomer), polarcompounds generated by chromatographic separation (more polar compound,less polar compound), equilibrium compounds, mixtures thereof atvoluntary ratios and racemic mixtures are also included in the presentinvention.

[Salts]

The salts of the present invention include all non-toxic salts, forexample, general salts or acid addition salts etc.

The compounds of the present invention represented by formula (I) may beconverted into the corresponding salts by conventional means. Non-toxicsalts or water-soluble salts are preferred. Suitable salts, for example,include: salts of alkali metals (e.g. potassium, sodium), salts ofalkaline earth metals (e.g. calcium, magnesium), ammonium salts, saltsof pharmaceutically acceptable organic amines (e.g. tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)amine, lysine, arginine,N-methyl-D-glucamine).

The compounds of the present invention represented by formula (I) may beconverted into the corresponding acid addition salts by conventionalmeans. Water-soluble salts are preferred. Suitable salts, for example,include: salts of inorganic acids e.g. hydrochloride, hydrobromide,sulfate, phosphate, nitrate; salts of organic acids e.g. acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isethionate, glucuronate, gluconate.

The compounds of the present invention represented by formula (I) andsalts thereof may be converted into the corresponding hydrates byconventional means.

All of the compounds of formula (I) or non-toxic salts thereof arepreferable, concretely, the compounds described in the example ornon-toxic salts thereof.

Quaternary ammonium salts of the compounds represented by formula (I)are the compounds where nitrogen of the compounds represented by formula(I) is quarternalized by R⁰.

R⁰ is C1-8 alkyl or C1-8 alkyl substituted by phenyl.

N-oxides of the compounds represented by formula (I) are the compoundswhere nitrogen of the compounds represented by formula (I) is oxidized.

[Methods for Preparation of the Compounds the Present Invention]

The compounds of the present invention of formula (I) may be prepared bythe following methods or the methods described in examples.

Among the compounds of the present invention of formula (I), thecompounds where nitrogens are not quaternary ammonium salts or N-oxides,i.e., the compounds of formula (I-1)

(wherein R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹ have the same meaning as R¹,R², R³, R⁴ and R⁵ respectively, and N¹ is nitrogen, wherein any nitrogenare not quaternary ammonium salts or N-oxides.)may be prepared by the following methods.

Among the compounds of the present invention represented by formula(I-1), the compounds in which any R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹ arenot a group containing carboxyl, hydroxy, amino or thiol, i.e., thecompounds of formula (I-1A)

(wherein R^(1-1A), R^(2-1A), R^(3-1A), R^(4-1A) and R^(5-1A) have thesame meaning as R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹ respectively, whereinall of them are not a group containing carboxyl, hydroxy, amino orthiol, and the other symbol have the same meanings as definedhereinbefore.)may be prepared by the following methods.

Among the compounds of formula (I-1A), the compounds in which R¹ doesnot represent hydrogen, i.e., the compounds of formula (I-1A-1)

(wherein R^(1-1A-1) have the same meaning as R^(1-1A), R^(1-1A-1) is nothydrogen, and the other symbols have the same meanings as definedhereinbefore.)may be prepared by cyclization of the compounds of formula (II-1)

(wherein X-L-—NH— is an amino terminus of aminated polystyrene resin,and the other symbols have the same meaning as defined hereinbefore.),or the compounds of formula (II-2)

(wherein T is C1-8 alkyl, C3-8 mono-carbocyclic ring or C1-8 alkylsubstituted by C3-8 mono-carbocyclic ring.).

The cyclization of compounds of formula (II-1) is well known. Forexample, it may be carried out by heating in an organic solvent (tolueneetc.) in the presence of acid (acetic acid, trifluoroacetic acid orhydrochloric acid etc.) at 60-120° C. This cyclization reaction iscarried out with the cleavage from polystyrene resin.

If necessary, the conversion to desired non-toxic salts may be carriedout by the conventional method in succession to this reaction.

The cyclization of compounds of formula (II-2) is well known. Forexample, it may be carried out by heating in an organic solvent(dichroloethane or toluene etc.), with tertiary amine (triethylamine ordiisopropylethylamine etc.) at 60-120° C. This cyclization reaction iscarried out with the cleavage of T group.

Among the compounds of formula (I-1A), the compounds in which R¹ ishydrogen, i.e., the compounds of formula (I-1A-2)

(wherein all of the symbols have the same meanings as definedhereinbefore.)may be prepared by the removal of an amino-protecting group of thecompounds in which R^(1A-1) is an amino-protecting group, i.e., thecompounds of formula (I-1A-1-1)

(wherein R^(1-1A-1-1) is an amino-protecting group, and the othersymbols have the same meaning as defined hereinbefore.).

A protecting group of amino includes, for example, benzyl,benzyloxycarbonyl, allyloxycarbonyl, t-butoxycarbonyl or trifluoroacetyletc.

The protecting group of amino includes the above one, in addition, theother protecting group which is removable selectively and easily, forexample, one described in T. W. Greene et. al., Protective Groups inOrganic Synthesis, Third Edition, Wiley-Interscience, New York, 1999.

The removal of a protecting group of amino is well known. For example,it is

-   (1) the alkaline hydrolysis,-   (2) the removal of a protecting group in an acidic condition,-   (3) the removal of a protecting group by hydrogenolysis or-   (4) the removal of a protecting group using metal complex etc.

Concrete descriptions of these methods are as follows:

-   (1) The removal of protecting group in an alkaline condition (e.g.    trifluoroacethyl group) may be carried out, for example, in an    organic solvent (methanol, tetrahydrofuran or dioxane etc.) with    hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide    or lithium hydroxide etc.), hydroxide of alkaline earth metal    (barium hydroxide or calcium hydroxide etc.), carbonate (sodium    carbonate or potassium carbonate etc.), or an aqueous solution    thereof or a mixture thereof at 0-40° C.-   (2) The removal of protecting group in an acidic condition (e.g.    t-butoxycarbonyl group) may be carried out, for example, in an    organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate    or anisole etc.), organic acid (acetic acid, trifluoroacetic acid or    methanesulfonic acid etc.) or inorganic acid (hydrochloric acid or    sulfuric acid etc.), or a mixture thereof (hydrogen bromide/acetic    acid etc.) at 0-100° C.-   (3) The removal of a protecting group by hydrogenolysis (e.g.    benzyl, benzyloxycarbonyl or allyloxycarbonyl) may be carried out,    for example, in a solvent (ether (tetrahydrofuran, dioxane,    dimethoxyethane or diethylether etc.), alcohol (methanol or ethanol    etc.), benzene (benzene or toluene etc.), ketone (acetone or    methylethylketone etc.), nitrile (acetonitrile etc.), amide    (dimethylformamide etc.), water, ethyl acetate, acetic acid or a    mixture thereof etc.) in the presence of a catalyst (palladium on    carbon, palladium black, palladium hydroxide, platinum oxide, Raney    nickel etc.), at atmospheric or positive pressure under an    atmosphere of hydrogen or in the presence of ammonium formate at    0-200° C.-   (4) The removal of a protecting group using metal complex may be    carried out, for example, in an organic solvent (dichloromethane,    dimethylformamide or tetrahydrofuran etc.) in the presence of a trap    reagent (tributyltin hydride or dimedone etc.) and/or an organic    acid (acetic acid etc.) with metal complex    (tetrakis(triphenylphosphine)palladium(0) complex etc.) at 0-40° C.

Moreover, the compounds of formula (I-1A-1) may be prepared with thecompounds of formula (I-1A-2) by the following methods of (a)-(g).

-   (a) Among the compounds of formula (I-1A-1), the compounds, in which    R^(1A-1) is C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, or C1-18    alkyl, C2-18 alkenyl or C2-18 alkynyl substituted by various    substituents, and in which R^(1A-1) bonds with N¹ through —CH₂—,    i.e., the compounds of formula (I-1A-1a)

(wherein R^(1-1A-1a) is C1-17 alkyl, C2-17 alkenyl, C2-17 alkynyl, orC1-17 alkyl, C2-17 alkenyl or C2-17 alkynyl substituted by 1-5 ofoptionally selected from (a) halogen, (b) —CONR⁷R⁸, (c) —COOR⁹, (d)—OR¹⁴, (e) —SR¹⁵, (f) —NR¹⁶R¹⁷, (g) —NR¹⁸COR¹⁹, (h) —SO₂NR²⁰R²¹, (i)—OCOR²², (j) —NR²³SO₂R²⁴, (k) —NR²⁵COOR²⁶, (l) —NR²⁷CONR²⁸R²⁹, (m) Cyc1, (n) keto, (o) —N(SO₂R²⁴)₂, wherein R^(1-1A-1a) is not a groupcontaining carboxyl, hydroxy, amino or thiol, and the other symbols havethe same meaning as defined hereinbefore.)may be prepared by the reductive amination of the compounds of formula(I-1A-2) with the compounds of formula (III)R^(1-1A-1a)—CHO  (III)(wherein all of the symbols have the same meanings as definedhereinbefore.).

The reductive amination is well known. For example, it may be carriedout in an organic solvent (dichloroethane, dichloromethane,dimethylformamide, acetic acid or a mixture thereof etc.) in thepresence of a reducing agent (sodium triacetoxyborohydride or sodiumcyanoborohydride etc.) at 0-40° C.

Moreover, the reductive amination may be carried out with the compoundsin which nitrogen of R¹ is oxidized to N-oxide.

-   (b) Among the compounds of formula (I-1A-1), the compounds, in which    R^(1A-1) is C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, or C1-18    alkyl, C2-18 alkenyl or C2-18 alkynyl substituted by various    substituents, and in which R^(1A-1) bonds with N¹ through    —CHR^(A-1b)— (wherein R^(A-1b) is C1-17 alkyl, C2-17 alkenyl or    C2-17 alkynyl.), i.e., the compounds of formula (I-1A-1b)

(wherein R^(A-1b) is C1-17 alkyl, C2-17 alkenyl or C2-17 alkynyl, andthe other symbols have the same meanings as defined hereinbefore.)may be prepared by reductive amination of the compounds of formula(I-1A-2) with the compounds of formula (IV)

(wherein all of the symbols have the same meanings as definedhereinbefore.).

The reductive amination is well known. For example, it may be carriedout in an organic solvent (dichloroethane or dichloromethane etc.) inthe presence of tertiary amine (triethylamine or diisopropylethylamineetc.) with Lewis acid (titanium tetrachloride etc.), at 0-40° C., andsubsequently by the addition of a reducing agent (sodiumtriacetoxyborohydride or sodium cyanoborohydride etc.) at 0-40° C.

-   (c) Among the compounds of formula (I-1A-1), the compounds in which    R^(1A-1) is COR⁶, i.e., the compounds of formula (I-1A-1c)

(wherein R^(6-1A-1c) has the same meaning as R⁶, wherein R^(6-1A-1c) isnot a group containing carboxyl, hydroxy, amino or thiol, and anynitrogen atoms are not quaternary ammonium salt nor N-oxide, and theother symbols have the same meaning as defined hereinbefore.)may be prepared by the amidation of the compounds of formula (I-1A-2)with the compounds of formula (V)

(wherein all of the symbols have the same meanings as definedhereinbefore.).

The amidation is well known. For example, it may be carried out in anorganic solvent (chloroform, dichloromethane, diethylether,tetrahydrofuran, dioxane or dimethylformamide etc.) in the presence oftertiary amine (isopropylethylamine, pyridine, triethylamine,dimethylaniline or dimethylaminopyridine etc.) or an aqueous alkalisolution (solution of bicarbonate or solution of sodium hydroxide etc.)at 0-40° C.

-   (d) Among the compounds of formula (I-1A-1), the compounds in which    R^(I-1A-1) is SO₂R¹⁰, i.e., the compounds of formula (I-1A-1d)

(wherein R^(10-1A-1d) has the same meaning as R¹⁰, wherein R^(10-1A-1d)is not a group containing carboxyl, hydroxy, amino or thiol, and anynitrogen atoms are not quaternary ammonium salt nor N-oxide, and theother symbols have the same meaning as defined hereinbefore.)may be prepared by the sulfonamidation of the compounds of formula(I-1A-2) with the compounds of formula (VI)

(wherein all of the symbols have the same meanings as definedhereinbefore.).

The sulfonamidation is well known. For example, it may be carried out inan inert organic solvent (chloroform, dichloromethane, dichloroethane,diethylether or tetrahydrofuran etc.) in the presence of tertiary amine(diisopropylethylamine, pyridine, triethylamine, dimethylaniline ordimethylaminopyridine etc.) at 0-40° C.

-   (e) Among the compounds of formula (I-1A-1), the compounds in which    R^(I-1A-1) is CONR⁷R⁸, i.e., the compounds of formula (I-1A-1e)

(wherein R^(7-1A-1e) has the same meaning as R⁷, R^(10-1A-1d) is not agroup containing carboxyl, hydroxy, amino or thiol, any nitrogen atomsare not quaternary ammonium salt nor N-oxide, and the other symbols havethe same meaning as defined hereinbefore.)may be prepared by the reaction of the compounds of formula (I-1A-2)with the compounds of formula (VII-1)

(wherein all of the symbols have the same meanings as definedhereinbefore.)or with the compounds of formula (VII-2)R^(7-1A-1e)—N═C═O  (VII-2)(wherein all of the symbols have the same meanings as definedhereinbefore.).

The reaction with the compounds of formula (VII-1) is well known. Forexample, it may be carried out in an organic solvent (chloroform,dichloromethane, diethylether or tetrahydrofuran etc.), in the presenceof a tertiary amine (isopropylethylamine, pyridine, triethylamine,dimethylaniline or dimethylaminopyridine etc.) at 0-40° C.

The reaction with the compounds of formula (VII-2) is well known. Forexample, it may be carried out in an inert organic solvent (chloroform,dichloromethane, dichloroethane, dimethylformamide, diethylether ortetrahydrofuran etc.) at 0-40° C.

-   (f) Among the compounds of formula (I-1A-1), the compounds in which    R^(1-1A-1) is —CH₂—CH(OH)—R^(A-1f)(R^(A-1f) is C1-16 alkyl, C2-16    alkenyl, C2-16 alkynyl, or C1-16 alkyl, C2-16 alkenyl or C2-16    alkynyl substituted by various substituents.), i.e., the compounds    of formula (I-1A-1f)

(wherein R^(A-1f) is C1-16alkyl, C2-16 alkenyl, C2-16 alkynyl, or C1-16alkyl, C2-16 alkenyl or C2-16 alkynyl substituted by 1-4 of optionallyselected from (a) halogen, (b) —CONR⁷R⁸, (c) —COOR⁹, (d) —OR¹⁴, (e)—SR¹⁵, (f) —NR¹⁶R¹⁷, (g) —NR¹⁸COR¹⁹, (h) —SO₂NR²⁰R²¹, (i) —OCOR²², (j)—NR²³SO₂R²⁴, (k) —NR²⁵COOR²⁶, (l) —NR²⁷CONR²⁸R²⁹, (m) Cyc 1, (n) keto,(o) —(SO₂R²⁴)₂, and any nitrogen atoms are not quaternary ammonium saltnor N-oxide and the other symbols have the same meaning as definedhereinbefore.)may be prepared by the reaction of the compounds of formula (I-1A-2)with the compounds formula (VIII)

(wherein all of the symbols have the same meanings as definedhereinbefore.).

The reaction is well known, and it may be carried out in an organicsolvent (methanol, ethanol, 2-propanol, tetrahydrofuran or acetonitlileetc.), in the presence or absence of a tertialy amine (triethylamine orN-methylmorpholine etc.) at 40-100° C.

-   (g) Among the compounds of formula (I-1A-1), the compounds in which    R^(1-1A-1) is —CH₂—C(═O)—R^(A-1g) (R^(A-1g) has the same meaning as    R^(A-1f)), i.e., the compounds of formula (I-1A-1g)

(wherein R^(A-1g) has the same meaning as R^(A-1f), and the othersymbols have the same meanings as defined hereinbefore.)may be prepared by the reaction of the compounds of formula (I-1A-2)with the compounds of formula (IX-1)

(wherein all of the symbols have the same meanings as definedhereinbefore.)or with the compounds of formula (IX-2)

(wherein all of the symbols have the same meanings as definedhereinbefore.).

The reaction is well known, and it may be carried out in an organicsolvent (chloroform, dichloromethane, diethylether, tetrahydrofuran,dioxane or dimethylformamide etc.) in the presence of a tertiary amine(isopropylethylamine, pyridine, triethylamine, dimethylaniline ordimethylaminopyridine etc.) at 0-40° C.

Moreover, the compounds of formula (I-1A-1) may be prepared by themethods described in (h).

-   (h) Among the compounds of formula (I-1A-1), the compounds in which    R^(1-1A-1) is 2-propenyl (—CH₂CH═CH₂), i.e., the compounds of    formula (I-1A-1h)

(wherein all of the symbols have the same meanings as definedhereinbefore.)may be prepared by the reaction of the compounds in which R^(1-1A-1) is2-propenyloxycarbonyl (—COO—CH₂CH═CH₂) among the compounds of formula(I-1A-1) prepared by the above method, i.e., the compounds of formula(I-1A-1-2)

(wherein all of the symbols have the same meanings as definedhereinbefore.) with a metal complex.

The reaction with a metal complex is well known, and it may be carriedout, for example, in an organic solvent (tetrahydrofuran or acetic acidetc.), with a metal complex (tetrakis(triphenylphosphine)palladium(0)complex etc.), at 0-40° C.

Among the compounds of formula (I-1), the compounds in which at leastone group of R¹, R², R³, R⁴ and R⁵ represents a group containingcarboxyl, hydroxy, amino or thiol, i.e., the compounds of formula (I-1B)

(wherein R^(1-1B), R^(2-1B), R^(3-1B), R^(4-1B) and R^(5-1B) have thesame meanings as R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹, respectively, at leastone group represents a group containing carboxyl, hydroxy, amino orthiol, and the other symbols have the same meanings as definedhereinbefore.)may be prepared by the removal of a protecting group of the compounds inwhich at least one group of R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ or R⁵⁻¹ represents agroup containing carboxyl, hydroxy, amino and thiol protected by aprotecting group, i.e., the compounds of formula (I-1A-3)

(wherein R^(1-1A-3), R^(2-1A-3), R^(3-1A-3), R^(4-1A-3) and R^(5-1A-3)have the same meanings of R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹, respectively,at least one group represents a group containing carboxyl, hydroxy,amino or thiol protected by a protecting group, and the other symbolshave the same meanings as defined hereinbefore.).

A protecting group of carboxyl includes, for example, methyl, ethyl,t-butyl, benzyl or allyl.

A protecting group of hydroxy includes, for example, methoxymethyl,2-tetrahydropyranyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetylor benzyl.

A protecting group of amino includes, for example, benzyloxycarbonyl,allyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl or9-fluorenylmethoxycarbonyl.

A protecting group of thiol includes, for example, benzyl,methoxybenzyl, acetoamidomethyl, triphenylmethyl or acetyl.

The protecting group of carboxyl, hydroxy, amino or thiol includes theabove one, and in addition the other protecting group which is removableselectively and easily, for example, one described in T. W. Greene et.al., Protective Groups in Organic Synthesis, Third Edition,Wiley-Interscience, New York, 1999.

The removal of a protecting group of amino may be carried out by themethod described hereinbefore.

The removal of a protecting group of carboxyl, hydroxy or thiol is wellknown. For example, it is

-   (1) the alkaline hydrolysis,-   (2) the removal of a protecting group in an acidic condition,-   (3) the removal of a protecting group by hydrogenolysis, or-   (4) the removal of a protecting group containing silyl or-   (5) the removal of a protecting group using metal complex etc.    Among these methods, (1), (2), (3) and (5) may be carried out by the    same methods of the removal of a protecting group of amino.

Concretely describing (4), the removal of a protecting group containingsilyl may be carried out, for example, in an organic solvent(tetrahydrofuran or acetonitrile etc.), with tetrabutylammoniumfluorideat 0-40° C.

As well known to the person in the art, the aimed compounds of thepresent invention may be prepared easily by choice of these removal of aprotecting group.

Moreover, the compounds of formula (I-1A-1) may be prepared by themethods described in (j)-(m) with the compounds of formula (I-1B-1)

(wherein R^(1-1B-1), R^(2-1B-1), R^(3-1B-1), R^(4-1B-1) and R^(5-1B-1)have the same meanings of R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹, respectively,at least one group represents a group containing amino, and the othersymbols have the same meanings as defined hereinbefore.).

-   (j) Among the compounds of formula (I-1A-1), the compounds in which    at least one group of R^(1-1A-1), R^(2-1A-1), R^(3-1A-1), R^(4-1A-1)    and R^(5-1A-1) represent a group containing amide, i.e., the    compounds of formula (I-1A-1j)

(wherein R^(1-1A-1j), R^(2-1A-1j), R^(3-1A-1j), R^(4-1A-1j) andR^(5-1A-1j) have the same meanings as R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹,respectively, at least one group represents a group containing amide,and the other symbols have the same meanings as defined hereinbefore.)may be prepared by the amidation of the compounds of formula (I-1B-1).

The amidation may be carried out by the method described hereinbefore.

-   (k) Among the compounds of formula (I-1A-1), the compounds in which    at least one group of R^(1-1A-1), R^(2-1A), R^(3-1A), R^(4-1A) and    R^(5-1A) represents a group containing sulfonamide, i.e., the    compounds of formula (I-1A-1k)

(wherein R^(1-1A-1k), R^(2-1A-1k), R^(3-1A-1k), R^(4-1A-1k) andR^(5-1A-1k) have the same meanings as R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹,respectively, at least one group represents a group containingsulfonamide, and the other symbols have the same meanings as definedhereinbefore.)may be prepared by the sulfonamidation of the compounds of formula(I-1B-1).

The sulfonamidation may be carried out the method describedhereinbefore.

-   (m) Among the compounds of formula (I-1A-1), the compounds in which    at least one group of R^(1-1A-1), R^(2-1A), R^(3-1A), R^(4-1A) and    R^(5-1A) represents a group containing urea, i.e., the compounds of    formula (I-1A-1m)

(wherein, R^(1-1A-1m), R^(2-1A-1m), R^(3-1A-1m), R^(4-1A-1m) andR^(5-1A-1m) have the same meanings as R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹,respectively, at least one group represents a group containing urea, andthe other symbols have the same meanings as defined hereinbefore.)may be prepared by the urea formation of the compounds of formula(I-1B-1).

The urea formation may be carried out the method described hereinbefore.

Among the compounds of formula (I-1), the compounds in which at leastone group of R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹ represents a groupcontaining hydroxy, and/or R¹ represents a group containing carboxyl,i.e., the compounds of formula (I-1B-2)

(wherein, R^(1-1B-2), R^(2-1B-2), R^(3-1B-2), R^(4-1B-2) and R^(5-1B-2)have the same meanings as R¹⁻¹, R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹, respectively,at least one group of R^(1-1B-2), R^(2-1B-2), R^(3-1B-2), R^(4-1B-2) andR^(5-1B-2) represents a group containing hydroxy and/or R^(1B-2)includes carboxyl, and the other symbols have the same meanings asdefined hereinbefore.)may be prepared by the method described in (n).

-   (n) Among the compounds of formula (I-1B-2), the compounds in which    R^(1-1B-2) is C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl or C1-18    alkyl, C2-18 alkenyl or C2-18 alkynyl substituted by various    substituent, and in which that R^(1-1B-2) bonds to N¹ atom through    —CH₂—, i.e., the compounds of formula (I-1B-1n)

(wherein R^(1-1B-2n) is C1-17alkyl, C2-17 alkenyl, C2-17 alkynyl, orC1-17 alkyl, C2-17 alkenyl or C2-17 alkynyl substituted by 1-5substituents optionally selected from (a) halogen, (b) —CONR⁷R⁸, (c)—COOR⁹, (d) —OR¹⁴, (e) —SR¹⁵, (f) —NR¹⁶R¹⁷, (g) —NR¹⁸COR¹⁹, (h)—SO₂NR²⁰R²¹, (i) —OCOR²², (j) —NR²³SO₂R²⁴, (k) —NR²⁵COOR²⁶, (l)—NR²⁷CONR²⁸R²⁹, (m) Cyc 1, (n) keto, (o) —N(SO₂R²⁴)₂, at least one groupof R^(1-1B-2n), R^(2-1B-2n), R^(3-1B-2n), R^(4-1B-2n) and R^(5-1B-2n)represents a group containing hydroxy, and/or R^(1B-2n) represents agroup containing carboxyl, and any nitrogen atoms are not quaternaryammonium salt nor N-oxide and the other symbols have the same meaning asdefined hereinbefore.)may be prepared by the reductive amination of the compounds in which R¹is hydrogen, and at least one group of R²⁻¹, R³⁻¹, R⁴⁻¹ and R⁵⁻¹represents a group containing hydroxy among the compounds of formula(I-1B) prepared by the above method, i.e., the compounds of formula(I-1B-3)

(wherein, all of the symbols have the same meanings as definedhereinbefore.)with the compounds of formula (X)R^(1-1B-2n)—CHO  (X)(wherein, all of the symbols have the same meanings as definedhereinbefore.).

The reductive amination may be carried out by the method describedhereinbefore.

Moreover, the reductive amination may be carried out in the compounds inwhich nitrogen in R¹ represents N-oxide.

Among the compounds of the present invention of formula (I), thecompounds in which at least one nitrogen is quaternary ammonium salt,i.e., the compounds of formula (I-2)

(wherein R¹⁻², R²⁻², R³⁻², R⁴⁻² and R⁵⁻² have the same meanings as R¹,R², R³, R⁴ and R⁵, respectively, and N² is nitrogen, at least onenitrogen is quaternary ammonium salt, and Q is halogen.)may be prepared by the reaction of the compounds of formula (I-1) withthe compounds of formula (XI)R⁰-Q  (XI)(wherein, R⁰ is C1-8 alkyl or C1-8 alkyl substituted by phenyl and Q ishalogen.).

The reaction is well known and it may be carried out, for example, in anorganic solvent (acetone, dimethylformamide or methyl ethyl ketone etc.)at 0-40° C.

Among the compounds of formula (I), the compounds in which at least onenitrogen represents N-oxide, i.e. the compounds of formula (I-3)

(wherein R¹⁻³, R²⁻³, R³⁻³, R⁴⁻³ and R⁵⁻³ have the same meanings of R¹,R², R³, R⁴ and R⁵, respectively, and N³ is nitrogen, and at least onenitrogen represents N-oxide.)may be prepared by the oxidation of the compounds of formula (I-1).

The oxidation is well known and it may be carried out, for example, in asuitable organic solvent (dichloromethane, chloroform, benzene, hexaneor t-butylalcohol etc.) in the presence of a excessive oxidizing reagent(hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate,peroxidized acid (for example, 3-chloroperbenzoic acid, peracetic acidetc.), OXONE (brand name, Potassium peroxymonosulfate is abbreviated asOXONE.), potassium permanganate or chromic acid etc.) at 20-60° C.

The compounds of the (II-1) may be prepared according to the followingReaction Schemes 1-3.

In Reaction Schemes, X is polystyrene resin, L is bivalent group, andthe other symbols have the same meanings as defined hereinbefore.

Bivalent group represented by L is, though it depends on the type of theused resin, e.g. methylene or Rink. Rink is4-(2,4-dimethoxybenzyl)phenoxymethyl.

In the present invention, e.g. aminomethylated polystyrene resin or9-fluorenylmethyloxycarbonylamino-Rink resin etc. can be used asterminal amino polystyrene resin.

As shown the following Reaction Scheme 4, the resin of formula (XVI) maybe prepared from aminomethylated polystyrene resin or9-fluorenylmethyloxycarbonylamino-Rink resin.

In the reaction using polystyrene resin in the present invention, thereaction products may be purified by the conventional methods, forexample, washing with a solvent (dimethylformamide, dichloromethane,methanol, tetrahydrofuran, toluene or acetic acid/toluene etc.) atseveral times. Moreover the obtained products may be purified byconventional techniques. For example, purification may be carried out bydistillation at atmospheric or reduced pressure, by high performanceliquid chromatography, by thin layer chromatography or by columnchromatography using silica gel or magnesium silicate, by washing or byrecrystallization.

The compounds of formula (II-2) may be prepared according to thefollowing Reaction Scheme 5.

The other starting materials and each test compounds in the presentinvention have been known per se or may be prepared by known methods.

[Toxicity]

The toxicity of the compounds of the present invention is very low andtherefore the compounds may be considered safe for pharmaceutical use.

INDUSTRIAL APPLICABILITY

[Application for Pharmaceuticals]

In animal included human, especially human, the compounds of the presentinvention of formula (I) are used for prevention and/or treatment forHIV infection or AIDS induced by the infection.

For the purpose above described, the compounds of the present inventionof formula (I), the quaternary ammonium salts thereof or the N-oxidesthereof, or the non-toxic salts thereof may be normally administeredsystemically or locally, usually by oral or parenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 mg to 1000 mg, by oraladministration, up to several times per day, and from 1 mg to 100 mg, byparenteral administration (preferably intravenous administration), up toseveral times per day, or continuous administration from 1 to 24 hoursper day from vein.

As mentioned above, the doses to be used depend upon various conditions.

Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered for example,in the form of solid for oral administration, liquid forms for oraladministration, injections, liniments or suppositories for parenteraladministration.

Solid forms for oral administration include compressed tablets, pills,capsules, dispersible powders, and granules. Capsules include hardcapsules and soft capsules.

In such solid forms, one or more of the active compound(s) may beadmixed with vehicles (such as lactose, mannitol, glucose,microcrystalline cellulose or starch), binders (such as hydroxypropylcellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate),disintegrants (such as cellulose calcium glycolate), lubricants (such asmagnesium stearate), stabilizing agents, and solution adjuvants (such asglutamic acid or aspartic acid) and prepared according to methods wellknown in normal pharmaceutical practice. The solid forms may, ifdesired, be coated with coating agents (such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), orbe coated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptablesolutions, suspensions, emulsions, syrups and elixirs. In such forms,one or more of the active compound(s) may be dissolved, suspended oremulsified into diluent(s) commonly used in the art (such as purifiedwater, ethanol or a mixture thereof). Besides such liquid forms may alsocomprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavoring agents, aroma,preservative or buffering agent.

Injections for parenteral administration include sterile aqueous,suspensions, emulsions and solid forms which are dissolved or suspendedinto solvent(s) for injection immediately before use. In injections, oneor more of the active compound(s) may be dissolved, suspended oremulsified into solvent(s). The solvents may include distilled water forinjection, saline, vegetable oil, propylene glycol, polyethylene glycol,alcohol, e.g. ethanol, or a mixture thereof. Injections may comprisesome additives, such as stabilizing agents, solution adjuvants (such asglutamic acid, aspartic acid or POLYSORBATE80 (registered trade mark)),suspending agents, emulsifying agents, soothing agent, buffering agents,preservative. They may be sterilized at a final step, or may be preparedand compensated according to sterile methods. They may also bemanufactured in the form of sterile solid forms such as freeze-driedproducts, which may be dissolved in sterile water or some other sterilediluent(s) for injection immediately before use.

Other forms for parenteral administration include liquids for externaluse, ointments and endermic liniments, inhalations, sprays,suppositories and pessaries for vaginal administration which compriseone or more of the active compound(s) and may be prepared by methodsknown per se.

Sprays may comprise additional substances other than diluents, such asstabilizing agents, such as sodium sulfate, isotonic buffers, such assodium chloride, sodium citrate or citric acid. For preparation of suchsprays, for example, the method described in the U.S. Pat. No. 2,868,691or 3,095,355 may be used.

The compound of the present invention represented by formula (I), aquaternary ammonium salt thereof, an N-oxide thereof or a non-toxic saltthereof may be used together with at least one member of otherpreventive and/or treating agent(s) for HIV infection (particularly anagent for preventive and/or treating agent AIDS). In that case, the drugas such may be mixed with pharmacologically acceptable excipient,binder, disintegrating agent, lubricant, stabilizer, solubilizer,diluent, etc. either separately or simultaneously to make into apharmaceutical preparation and that can be administered either orally orparenterally as a pharmaceutical composition for prevention and/ortreatment of HIV infection.

The compound of the present invention represented by formula (I), aquaternary ammonium salt thereof, an N-oxide thereof or a non-toxic saltthereof has an infection inhibiting activity to HIV-I which acquiredresistance to other agent for preventive and/or treating HIV infection(particularly, an agent for preventive and/or treating agent AIDS).Therefore, it is also able to be used for HIV-infected patients to whomother agent for preventive and/or treating HIV infection is no longereffective. In that case, although the compound of the present inventionmay be used solely, it may be also used together with an agent forpreventive and/or treating HIV infection where infected HIV-1 strainacquired resistance or with other drugs.

The present invention covers the case where the compound represented byformula (I), a quaternary ammonium salt thereof, an N-oxide thereof or anon-toxic salt thereof is combined with a drug which does not inhibitthe HIV infection whereby preventive and/or treating effect for HIVinfection is enhanced as compared with a single preparation.

Examples of other agent for preventive and/or treating HIV infectionused for a combination with the compound of the present inventionrepresented by formula (I), a quaternary ammonium salt thereof, anN-oxide thereof or a non-toxic salt thereof are reverse transcriptaseinhibitor, protease inhibitor, chemokine antagonist (such as CCR2antagonist, CCR3 antagonist, CCR4 antagonist, CCR5 antagonist and CXCR4antagonist), fusion inhibitor, antibody to surface antigen of HIV-1 andvaccine of HIV-1.

Reverse transcriptase inhibitors are concretely (1)nucleoside/nucleotide reverse transcriptase inhibitors: zidovudine(brand name: Retrovir), didanosine (brand name: Videx), zalcitabine(brand name: HIVID), stavudine (brand name: Zerit), lamivudine (brandname: Epivir), abacavir (brand name: Ziagen), adefovir, adefovirdipivoxil, emtricitabine (brand name: Coviracil) or PMPA (brand name:Tenofovir) etc. and (2) nonnucleoside reverse transcriptase inhibitors:nevirapine (brand name: Viramune), delavirdine (brand name: Rescriptor),efavirenz (brand name: Sustiva, Stocklin) or capravirine (AG1549) etc.

Protease inhibitors are concretely indinavir (brand name: Crixivan),ritonavir (brand name: Norvir), nelfinavir (brand name: Viracept),saquinavir (brand name: Invirase, Fortovase), amprenavir (brand name:Agenerase), Iopinavir (brand name: Kaletra) or tipranavir etc.

As chemokine antagonists, internal ligand of chemokine receptor, itsderivatives, its non-peptide low molecular compound or antibody ofchemokine receptor are included.

The examples of internal ligand of chemokine receptor are concretely,MIP-1α, MIP-1β, RANTES, SDF-1α, SDF-1β, MCP-1, MCP-2, MCP-4, Eotaxin andMDC etc.

The derivatives of internal ligand are concretely, AOP-RANTES,Met-SDF-1α, Met-SDF-1β etc.

Antibodies of chemokine receptor are concretely, Pro-140 etc.

CCR2 antagonists are concretely written in specification of WO99/07351,WO99/40913, WO00/46195, WO00/46196, WO00/46197, WO00/46198, WO00/46199,WO00/69432 or WO00/69815 or in Bioorg. Med. Chem. Lett., 10, 1803 (2000)etc.

CCR3 antagonists are concretely written in specification of DE19837386,WO99/55324, WO99/55330, WO00/04003, WO00/27800, WO00/27835, WO00/27843,WO00/29377, WO00/31032, WO00/31033, WO00/34278, WO00/35449, WO00/35451,WO00/35452, WO00/35453, WO00/35454, WO00/35876, WO00/35877, WO00/41685,WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/53172, WO00/53600,WO00/58305, WO00/59497, WO00/59498, WO00/59502, WO00/59503, WO00/62814,WO00/73327 or WO01/09088 etc.

CCR5 antagonists are concretely written in specification of WO99/17773,WO99/32100, WO00/06085, WO00/06146, WO00/10965, WO00/06153, WO00/21916,WO00/37455, EP1013276, WO00/38680, WO00/39125, WO00/40239, WO00/42045,WO00/53175, WO00/42852, WO00/66551, WO00/66558, WO00/66559, WO00/66141,WO00/68203, JP2000309598, WO00/51607, WO00/51608, WO00/51609,WO00/51610, WO00/56729, WO00/59497, WO00/59498, WO00/59502, WO00/59503,WO00/76933, WO98/25605 or WO99/04794, WO99/38514 or in Bioorg. Med.Chem. Lett., 10, 1803 (2000) etc.

CXCR4 antagonists are concretely AMD-3100, T-22, KRH-1120 or thecompounds written in specification of WO00/66112 etc.

Fusion Inhibitors are concretely, T-20(Pentafuside) and T-1249 etc.

The examples of combination agents written above are intended toillustrate the present invention, but do not limit them.

The typical examples of the usual the dosage level in clinical trials ofreverse transcriptase inhibitors or protease inhibitors written beloware intended to illustrate the present invention, but do not limit them.

-   Zidovudine: 100 mg capsule, 200 mg per dose, 3 times per day;    -   300 mg tablet, 300 mg per dose, twice per day;-   didanosine: 25-200 mg tablet, 125-200 mg per dose, twice per day;-   zalcitabine: 0.375-0.75 mg tablet, 0.75 mg per dose, 3 times per    day;-   stavudine: 15-40 mg capsule, 30-40 mg per dose, twice per day;-   lamivudine: 150 mg tablet, 150 mg per dose, twice per day;-   abacavir: 300 mg tablet, 300 mg per dose, twice per day;-   nevirapine: 200 mg tablet, 200 mg per dose, once per day for 14 days    and then twice per day;-   delavirdine: 100 mg tablet, 400 mg per dose, 3 times per day;-   efavirenz: 50-200 mg capsule, 600 mg per dose, once per day;-   indinavir: 200-400 mg capsule, 800 mg per dose, 3 times per day;-   ritonavir: 100 mg capsule, 600 mg per dose, twice per day;-   nelfinavir: 250 mg tablet, 750 mg per dose, 3 times per day;-   saquinavir: 200 mg capsule, 100 or 200 mg per dose, 3 times per day;-   amprenavir: 50-150 mg tablet, 100 or 200 mg per dose, twice per day.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Reference Examples and Examples are intended to illustratethe present invention, but do not limit them.

In chromatographic separations and TLC, the solvents in parenthesis showthe eluting and developing solvents and the ratios of the solvents usedare by volume.

The solvents in parenthesis in NMR show the solvents used formeasurement.

R* and S* do not represent the absolute position but the relativeposition.

REFERENCE EXAMPLE 1 Preparation of Resin (2)

Aminomethylpolystyrene resin hydrochloride (Resin (1); X is polystyreneresin.) (30.0 g) (1% divinylbenzene copolymer, Watanabe Kagaku, CatalogNo A00062) was washed with dimethylformamide (300 ml), 10%diisopropylethylamine-dimethylformamide solution (300 ml) anddimethylformamide (300 ml) successively, and was suspended indimethylformamide (200 ml). To the suspension were added formic acid(10.2 ml) and diisopropylcarbodiimide (42.3 ml) under cooling with ice,and it was stirred for 1 hour at room temperature. The resin wascollected by filtration from the reaction solution, and was washed withdimethylformamide (250 ml×3), dichloromethane (250 ml×4), methanol (250ml×2) and dichloromethane (250 ml×4) to give Resin (2).

IR (KBr): ν 1682 cm⁻¹.

REFERENCE EXAMPLE 2 Preparation of Resin (3)

To a suspension of Resin (2) prepared in Reference Example 1 indichloromethane (300 ml) were added triethylamine (18.8 ml), carbontetrachloride (13.0 ml) and triphenylphosphine (35.4 g), and it wasrefluxed for 1 hour. The reaction solution was cooled to roomtemperature, and the resin was collected by filtration. The resin waswashed with dichloromethane (250 ml×3), methanol (250 ml×1) anddichloromethane (250 ml×2) and dried under reduced pressure to giveResin (3) (28.2 g).

IR (KBr): ν 2147 cm⁻¹.

REFERENCE EXAMPLE 3 Preparation of Compound (1)

To a suspension of Resin (3) prepared in Reference Example 2 (2.5 g) intetrahydrofuran/methanol (1:1; 25 ml) were addedN-allyloxycarbonyl-4-piperidone (2.15 g), n-propylamine (0.97 ml) andN-(t-butyloxycarbonyl)leucine (2.93 g), and it was stirred for 16 hoursat 65° C. The reaction solution was cooled to room temperature, and theresin was collected by filtration. The obtained resin was washed withtetrahydrofuran (25 ml×2), methanol (25 ml×2) and dichloromethane (25ml×2) to give compound (1).

REFERENCE EXAMPLE 4 Preparation of Compound (2)

To a suspension of the compound (1) prepared in Reference Example 3 indichloromethane (25 ml) were added acetic acid (0.81 ml), tributyltinhydride (1.90 ml) and tetrakis(triphenylphosphine)palladium (0) complex(270 mg), and it was stirred for 6 hours at room temperature. The resinwas collected by filtration from the reaction solution, and was washedwith dichloromethane (25 ml×3), methanol (25 ml×2), dichloromethane (25ml×2) and dimethylformamide (25 ml×3) to give compound (2).

REFERENCE EXAMPLE 5 Preparation of Compound (3)

To a suspension of the compound (2) prepared in Reference Example 4 indimethylformamide (25 ml) were added3,5-dimethyl-1-phenyl-4-formylpyrazole (1.41 g), sodiumtriacetoxyborohydride (1.50 g) and acetic acid (0.2 ml), and it wasstirred for 16 hours at room temperature. The resin was collected byfiltration from the reaction solution, and was washed withdimethylformamide (20 ml×2), dichloromethane (20 ml×2), methanol (20ml×2) and dichloromethane (20 ml×4) to give compound (3).

REFERENCE EXAMPLE 6 Preparation of Compound (4)

The compound (3) prepared in Reference Example 5 was suspended in 50%trifluoroacetic acid-dichloromethane solution (25 ml), and thesuspension was stirred for 5 minutes at room temperature. The reactionsolution was filtrated. The obtained resin was suspended in 50%trifluoroacetic acid-dichloromethane solution (25 ml), and it wasstirred for 30 minutes at room temperature. The resin was collected byfiltration from the reaction solution and was washed withdichloromethane (25 ml×4), toluene (25 ml×4), and 1.25 M aceticacid-toluene solution (25 ml×1) to give compound (4).

REFERENCE EXAMPLE 7 Preparation of Resin (5)

9-fluorenylmethyloxycarbonylamino-Rink resin (Resin (4)) (5.0 g) (1%divinylbenzene copolymer, Watanabe Kagaku, Catalog No A00102) was washedwith dimethylformamide (50 ml×3), and 20% piperidine-dimethylformamidesolution (50 ml×2). The washed resin was suspended in 20%piperidine-dimethylformamide solution (50 ml), and the suspension wasstirred for 30 minutes at room temperature. The reaction solution wasfiltrated. The obtained resin was washed with dimethylformamide (50ml×5). To a suspension of the washed resin in dimethylformamide (20 ml)was added ethyl formate (30 ml), and it was refluxed for 6 hours. Thereaction solution was cooled to room temperature and was filtrated. Thefiltrated resin was washed with dimethylformamide (50 ml×2),dichloromethane (50 ml×4), methanol (50 ml×4) and dichloromethane (50ml×4), and dried under reduced pressure to give Resin (5) (4.34 g).

IR (KBr): ν 1693 cm⁻¹.

REFERENCE EXAMPLE 8 Preparation of Resin (6)

By the same procedure as described in Reference Example 2 using Resin(4) prepared in Reference Example 7 (4.0 g), Resin (6) (3.56 g) wasobtained.

IR (KBr): ν 2136 cm⁻¹.

REFERENCE EXAMPLE 9 Preparation of Compound (5)

By the same procedure as described in Reference Example 3 using Resin(6) prepared in Reference Example 8 (1.0 g),N-(6-phenylhexyl)-4-piperidone (0.44 g), n-propylamine (0.14 ml) andN-(t-butyloxycarbonyl)-L-leucine (0.42 g), compound (5) was obtained.

REFERENCE EXAMPLE 10 Preparation of Compound (6)

To a suspension of the compound (5) prepared in Reference Example 9 in1.5 M 2,6-lutidine-dichloromethane (4 ml) was added 1M trimethylsilyltrifluoromethanesulfonate-dichloromethane solution (4 ml), and it wasstirred for 30 minutes at room temperature. The resin was collected byfiltration from the reaction solution. The obtained resin was againsuspended in 1.5 M 2,6-lutidine-dichloromethane solution (4 ml), and 1Mtrimethylsilyl trifluoromethanesulfonate-dichloromethane solution (4 ml)was added thereto. It was stirred for 30 minutes at room temperature.The resin was collected by filtration from the reaction solution. Theresin was washed with dichloromethane (6 ml×4), methanol (6 ml×4), andtoluene (6 ml×5) to give compound (6).

EXAMPLE 19-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-2,5-dioxo-3-(2-methyl-1-propyl)-1-propyl-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

The compound (4) prepared in Reference Example 6 was suspended in 1.25 Macetic acid-toluene solution (25 ml), and the suspension was stirred for24 hours at 90° C., and was stirred for 16 hours at room temperature.The reaction solution was filtrated. The obtained resin was washed withchloroform-methanol (1:1; 20 ml×2). The filtrate and the washings wereconcentrated. The residue was purified by column chromatography onsilica gel (Fuji Silysia Chemical Ltd., FL60D;chloroform:methanol=30:1). A solution of the obtained residue inmethanol was acidified by adding 1N hydrochloric acid, and wasconcentrated to give the title compound (703 mg) having the followingphysical data.

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.68-7.50 (m,5H), 4.36 (s, 2H), 4.03 (dd, J=7.8, 5.2 Hz, 1H), 3.83 (m, 2H), 3.64 (m,2H), 3.47 (m, 2H), 2.64 (m, 2H), 2.49 (s, 3H), 2.44 (s, 3H), 2.20 (m,2H), 1.81 (m, 1H), 1.68 (m, 2H), 1.60 (m, 2H), 1.05-0.90 (m, 9H); IR(KBr): ν 3424, 3215, 2960, 2873, 2492, 1671, 1645, 1554, 1501, 1468,1418, 1370, 1330, 1297, 1243, 1148, 958, 928, 754, 698 cm⁻¹; MS (MALDI,Pos., α-CHCA): 488 (M+Na)⁺, 466 (M+H)⁺, 185. elemental analysis:calculated (C₂₇H₃₉N₅O₂.2HCl) C, 60.22%; H, 7.67%; N, 13.00%. Found C,59.89%; H, 7.67%; N, 12.79%.

EXAMPLE 2(1) TO 2(3)

By the same procedure as described in Reference Example 3→ReferenceExample 4 using Resin (3) prepared in Reference Example 2 andN-allyloxycarbonyl-4-piperidone, using the corresponding compoundsrespectively instead of n-propylamine and N-(t-butyloxycarbonyl)leucine,and furthermore by the same procedure as described in Reference Example5→Reference Example 6→Example 1 using the corresponding compound insteadof 3,5-dimethyl-1-phenyl-4-formylpyrazole, the following compounds ofthe present invention were obtained.

EXAMPLE 2(1)9-(1,4-benzodioxan-6-ylmethyl)-1-butyl-3-cyclohexylmethyl-2,5-dioxo-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.08 (d, J=2.2Hz, 1H), 6.99 (dd, J=8.0, 2.2 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 4.27 (s,4H), 4.23 (s, 2H), 4.04 (dd, J=7.6, 4.8 Hz, 1H), 3.74 (m, 2H), 3.60-3.35(m, 4H), 2.43 (m, 2H), 2.15 (m, 2H), 1.90-1.60 (m, 7H), 1.60-1.45 (m,2H), 1.45-1.30 (m, 2H), 1.30-1.10 (m, 4H), 1.10-0.80 (m, 5H); IR (KBr):ν 3436, 2926, 2852, 2511, 1675, 1645, 1591, 1511, 1418, 1374, 1294,1261, 1068, 1050, 930, 888 cm⁻¹; MS (MALDI, Pos., α-CHCA): 484 (M+H)⁺,149. elemental analysis: calculated (C₂₈H₄₁N₃O₄.HCl) C, 64.66%; H,8.14%; N, 8.08%. Found C, 64.00%; H, 7.94%; N, 7.90%.

EXAMPLE 2(2)1-butyl-3-cyclohexylmethyl-2,5-dioxo-9-(2-phenylimidazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.05-7.94 (m,3H), 7.75-7.60 (m, 3H), 4.59 (s, 2H), 4.05 (dd, J=7.4, 4.8 Hz, 1H), 3.88(m, 2H), 3.65 (m, 2H), 3.51 (m, 2H), 2.68 (m, 2H), 2.19 (m, 2H),1.90-1.60 (m, 6H), 1.60-1.45 (m, 3H), 1.45-1.30 (m, 3H), 1.30-1.10 (m,3H), 1.10-0.80 (m, 5H); IR (KBr): ν 3423, 2927, 2854, 2664, 1672, 1644,1421, 1373, 1177, 775, 709, 688 cm⁻¹; MS (MALDI, Pos., α-CHCA): δ 492(M+H)⁺. elemental analysis: calculated (C₂₉H₄₁N₅O₂.2HCl.2.8H₂O) C,56.63%; H, 7.96%, N, 11.39%. Found C, 56.90%; H, 7.23%; N, 10.78%.

EXAMPLE 2(3)1-butyl-3-(2-methyl-1-propyl)-2,5-dioxo-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54 (d, J=8.8Hz, 2H), 7.40 (m, 2H), 7.18 (m, 1H), 7.11-7.00 (m, 4H), 4.33 (s, 2H),4.01 (dd, J=7.6, 4.8 Hz, 1H), 3.80 (m, 2H), 3.60-3.35 (m, 4H), 2.46 (m,2H), 2.18 (m, 2H), 1.80 (m, 1H), 1.70 (m, 1H), 1.54 (m, 2H), 1.37 (m,3H), 1.00-0.90 (m, 9H); IR (KBr): ν 3440, 3221, 3066, 2957, 2871, 2559,1673, 1590, 1509, 1489, 1419, 1371, 1329, 1242, 1172, 873, 693 cm⁻¹; MS(MALDI, Pos., α-CHCA): 478 (M+H)⁺, 183. elemental analysis: calculated(C₂₉H₃₉N₃O₃.HCl) C, 67.75%; H, 7.84%; N, 8.17%. Found C, 67.29%; H,7.70%; N, 8.06%.

EXAMPLE 2(4)(3S)-2,5-dioxo-3-(2-methylpropyl)-9-(6-phenylhexyl)-1-propyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 1 using the compound (6)prepared in Reference Example 10, the title compound (69 mg) having thefollowing physical data was obtained.

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.18 (m, 5H),4.02 (dd, J=7.6, 4.8 Hz, 1H), 3.70 (m, 2H), 3.56 (m, 2H), 3.39 (m, 2H),3.11 (m, 2H), 2.63 (dd, J=7.8, 7.2 Hz, 2H), 2.48 (m, 2H), 2.17 (m, 2H),1.95-1.50 (m, 9H), 1.42 (m, 4H), 1.00-0.89 (m, 9H); IR (KBr): ν 3435,3205, 3082, 3026, 2935, 2870, 2493, 2361, 1674, 1454, 1417, 1370, 1331,1155, 1071, 1004, 961, 750, 700 cm⁻¹; MS (FAB, Pos.,glycerin-m-nitrobenzyl alcohol): 442 (M+H)⁺, 232, 171, 79 (base peak).elemental analysis: calculated (C₂₇H₄₃N₃O₂.HCl) C, 67.83%; H, 9.28%; N,8.79%. Found C, 67.56%; H, 9.50%; N, 8.71%.

EXAMPLE 2(5)(3R)-2,5-dioxo-3-(2-methylpropyl)-9-(6-phenylhexyl)-1-propyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Reference Example 9→ReferenceExample 10→Example 1 using Resin (6) prepared in Reference Example 8(1.0 g), N-(6-phenylhexyl)-4-piperidone (0.44 g), n-propylamine (0.14ml) and N-(t-butyloxycarbonyl)-D-leucine (0.42 g), the title compound(63 mg) having the following physical data was obtained.

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.18 (m, 5H),4.02 (dd, J=7.6, 4.6 Hz, 1H), 3.70 (m, 2H), 3.56 (m, 2H), 3.39 (m, 2H),3.11 (m, 2H), 2.63 (dd, J=7.8, 7.2 Hz, 2H), 2.48 (m, 2H), 2.17 (m, 2H),1.95-1.50 (m, 9H), 1.42 (m, 4H), 1.00-0.89 (m, 9H); IR (KBr): ν 3441,3204, 3082, 3026, 2935, 2870, 2660, 2499, 2413, 2361, 1674, 1455, 1417,1370, 1330, 1267, 1205, 1154, 1070, 1003, 960, 928, 899, 750, 700 cm⁻¹;

MS (FAB, Pos., glycerin-m-nitrobenzyl alcohol): 442 (M+H)⁺ (base peak),294, 232, 202, 171, 79. elemental analysis: calculated (C₂₇H₄₃N₃O₂.HCl)C, 67.83%; H, 9.28%; N, 8.79%. Found C, 67.52%; H, 9.51%; N, 8.70%.

EXAMPLE 3(1) TO 3(4)

By the same procedure as described in Reference Example 3→ReferenceExample 4 using Resin (3) prepared in Reference Example 2 andN-allyloxycarbonyl-4-piperidone, using the corresponding compoundsrespectively instead of n-propylamine and N-(t-butyloxycarbonyl)leucine,and furthermore by the same procedure as described in Reference Example5→Reference Example 6→Example 1 using the corresponding compound insteadof 3,5-dimethyl-1-phenyl-4-formylpyrazole, the following compounds ofthe present invention were obtained.

EXAMPLE 3(1)1-butyl-9-((3,5-dimethyl-1-phenyl)-4-pyrazolyl)methyl)-2,5-dioxo-3-(2-methyl-1-propyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.52 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.70-7.48 (m,5H), 4.35 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz, 1H), 3.83 (m, 2H), 3.63 (m,2H), 3.51 (m, 2H), 2.64 (m, 2H), 2.48 (s, 3H), 2.43 (s, 3H), 2.20 (m,2H), 1.81 (m, 2H), 1.71 (m, 2H), 1.55 (m, 2H), 1.50-1.35 (m, 4H),1.05-0.90 (m, 6H).

EXAMPLE 3(2)1-butyl-3-cyclohexylmethyl-2,5-dioxo-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.73 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.74-7.56 (m,1H), 7.53 (d, J=8.8 Hz, 2H), 7.40 (m, 2H), 7.18 (m, 1H), 7.10-7.00 (m,3H), 4.33 (s, 2H), 4.04 (dd, J=7.4, 4.8 Hz, 1H), 3.80 (m, 2H), 3.60-3.35(m, 4H), 2.43 (m, 2H), 2.17 (m, 2H), 1.90-1.60 (m, 7H), 1.60-1.45 (m,2H), 1.45-1.30 (m, 2H), 1.30-1.15 (m, 4H), 1.10-0.80 (m, 5H).

EXAMPLE 3(3)9-(1,4-benzodioxan-6-ylmethyl)-1-butyl-3-(2-methyl-1-propyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.08 (d, J=2.2Hz, 1H), 7.01 (dd, J=8.2, 2.2 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 4.27 (s,4H), 4.23 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.72 (m, 2H), 3.55-3.35(m, 4H), 2.43 (m, 2H), 2.16 (m, 2H), 1.80 (m, 1H), 1.67 (m, 2H), 1.55(m, 2H), 1.37 (m, 2H), 1.00-0.90 (m, 9H).

EXAMPLE 3(4)9-(4-benzyloxyphenylmethyl)-1-butyl-2,5-dioxo-3-(2-methyl-1-propyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54-7.25 (m,7H), 7.10 (m, 2H), 5.13 (s, 2H), 4.27 (s, 2H), 4.00 (dd, J=8.2, 4.8 Hz,1H), 3.72 (m, 2H), 3.55-3.35 (m, 4H), 2.42 (m, 2H), 2.16 (m, 2H),1.90-1.25 (m, 7H), 1.00-0.90 (m, 9H).

EXAMPLE 41-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(6-phenylhexyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Reference Example 3→ReferenceExample 6→Example 1 using Resin (3) prepared in Reference Example 2,N-(6-phenylhexyl)-4-piperidone, n-butylamine andN-(t-butyloxycarbonyl)leucine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.62 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.30-7.06 (m,5H), 4.02 (dd, J=7.8, 4.8 Hz, 1H), 3.70 (m, 2H), 3.56 (m, 2H), 3.43 (m,2H), 3.11 (m, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.46 (m, 2H), 2.18 (m, 2H),1.95-1.50 (m, 9H), 1.50-1.25 (m, 6H), 0.97 (m, 9H).

EXAMPLE 5(1) TO 5(12)

By the same procedure as described in Reference Example 9→ReferenceExample 10→Example 1 using the corresponding compounds respectivelyinstead of N-(6-phenylhexyl)-4-piperidone, n-propylamine andN-(t-butyloxycarbonyl)-L-leucine, using Resin (6) prepared in ReferenceExample 8, the following compounds of the present invention wereobtained.

EXAMPLE 5(1)(3S)-1-(2-methylpropyl)-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 10H),5.07 (s, 2H), 4.12 (m, 1H), 3.94 (m, 1H), 3.61 (m, 5H), 3.39 (m, 2H),3.13 (m, 4H), 2.31 (m, 4H), 1.92 (m, 3H), 1.51 (m, 2H), 1.39 (m, 2H),0.93 (t, J=6.4 Hz, 6H).

EXAMPLE 5(2)(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 10H),5.06 (m, 2H), 4.07 (m, 1H), 3.86 (m, 1H), 3.76 (m, 1H), 3.63 (m, 2H),3.37 (m, 4H), 3.12 (m, 4H), 2.43 (m, 2H), 2.21 (m, 2H), 1.86 (m, 2H), δ1.55 (m, 4H), 1.37 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 5(3)(3R)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 10H),5.06 (s, 2H), 4.07 (m, 1H), 3.86 (m, 1H), 3.76 (m, 1H), 3.63 (m, 2H),3.37 (m, 4H), 3.12 (m, 4H), 2.43 (m, 2H), 2.21 (m, 2H), 1.86 (m, 2H),1.55 (m, 4H), 1.37 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 5(4)(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(3-phenylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 5H),7.26 (m, 5H), 5.05 (s, 2H), 4.05(m, 1H), 3.85-3.30 (m, 6H), 3.12 (m,4H), 2.73 (t, J=7.6 Hz, 2H), 2.44 (m, 2H), 2.13 (m, 4H), 1.85 (m, 2H),1.54 (m, 4H), 1.38 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 5(5)(3R)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(3-phenylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 5H),7.26 (m, 5H), 5.05 (s, 2H), 4.05 (m, 1H), 3.85-3.30 (m, 6H), 3.12 (m,4H), 2.73 (t, J=7.2 Hz, 2H), 2.44 (m, 2H), 2.13 (m, 4H), 1.85 (m, 2H),1.54 (m, 4H), 1.38 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 5(6)(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxyarbonyl)aminobutyl)-9-(4-phenylbutyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 5H),7.22 (m, 5H), 5.06 (s, 2H), 4.05(m, 1H), 3.85-3.38 (m, 6H), 3.12 (m,4H), 2.70 (m, 2H), 2.40 (m, 2H), 2.18 (m, 2H), 1.74 (m, 6H), 1.54 (m,4H), 1.38 (m, 2H), 0.94 (t, J=7.0 Hz, 3H).

EXAMPLE 5(7)(3R)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(4-phenylbutyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 5H),7.22 (m, 5H), 5.06 (s, 2H), 4.05(m, 1H), 3.85-3.38 (m, 6H), 3.12 (m,4H), 2.70 (m, 2H), 2.40 (m, 2H), 2.18 (m, 2H), 1.74 (m, 6H), 1.54 (m,4H), 1.38 (m, 2H), 0.94 (t, J=7.0 Hz, 3H).

EXAMPLE 5(8)(3S)-1-benzyl-2,5-dioxo-3-(2-methylpropyl)-9-benzyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.48 (m, 5H),7.23 (m, 5H), 4.82 (m, 2H), 4.31 (s, 2H), 4.17 (dd, J=8.0, 4.6 Hz, 1H),3.72 (m, 2H), 3.40 (m, 2H), 2.52 (m, 2H), 2.08 (m, 2H), 2.00-1.60 (m,3H), 0.98 (d, J=6.0 Hz, 6H).

EXAMPLE 5(9)(3R)-1-benzyl-2,5-dioxo-3-(2-methylpropyl)-9-benzyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.48 (m, 5H),7.23 (m, 5H), 4.82 (m, 2H), 4.31 (s, 2H), 4.17 (dd, J=8.0, 4.6 Hz, 1H),3.72 (m, 2H), 3.40 (m, 2H), 2.52 (m, 2H), 2.08 (m, 2H), 2.00-1.60 (m,3H), 0.98 (d, J=6.0 Hz, 6H).

EXAMPLE 5(10)(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(2-(2-phenyl-5-methyloxazol-4-yl)ethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.01 (m, 2H),7.53 (m, 3H), 7.34 (m, 5H), 5.07 (s, 2H), 4.08 (dd, J=5.4, 4.4 Hz, 1H),4.00-3.60 (m, 4H), 3.47 (m, 4H), 3.13 (m, 4H), 2.56 (m, 2H), 2.46 (s,3H), 2.25 (m, 2H), 1.87 (m, 2H), 1.75-1.25 (m, 6H), 0.94 (t, J=7.2 Hz,3H).

EXAMPLE 5(11)(3S)-1-propyl-2,5-dioxo-3-(4-(N-(2-chlorophenylmethyl)oxycarbonyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 9H),5.17 (s, 2H), 4.08 (dd, J=5.2, 4.8 Hz, 1H), 3.80 (m, 2H), 3.65 (m, 3H),3.39 (m, 3H), 3.14 (m, 4H), 2.50 (m, 2H), 2.22 (m, 2H), 1.85 (m, 2H),1.70-1.20 (m, 6H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 5(12)(3S)-1-propyl-2,5-dioxo-3-[3-(3-(2,4,6-trimethylphenylsulfonyl)guanidino)propyl]-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.32 (m, 5H),7.05 (s, 2H), 4.10 (m, 1H), 3.88 (m, 1H), 3.67 (m, 3H), 3.40 (m, 4H),3.18 (m, 4H), 2.66 (s, 6H), 2.51 (m, 2H), 2.31 (s, 3H), 2.21 (m, 2H),1.82 (m, 2H), 1.60 (m, 4H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 6(1) TO 6(32)

By the same procedure as described in Reference Example 3→ReferenceExample 4 using Resin (3) prepared in Reference Example 2,N-allyloxycarbonyl-4-piperidone, the corresponding amine derivatives andthe corresponding amino acid derivatives, and furthermore by the sameprocedure as described in Reference Example 5→Reference Example6→Example 1 using the corresponding aldehyde derivatives, the followingcompounds of the present invention were obtained.

EXAMPLE 6(1)1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.55 (m, 2H),7.40 (m, 2H), 7.18 (m, 1H), 7.05 (m, 4H), 4.33 (s, 2H), 4.01 (dd, J=7.6,4.8 Hz, 1H), 3.79 (m, 2H), 3.60-3.30 (m, 4H), 2.46 (m, 2H), 2.17 (m,2H), 1.95-1.40 (m, 5H), 0.94 (m, 9H).

EXAMPLE 6(2)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.8Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.29 (s, 2H), 4.04 (dd, J=7.6, 4.8 Hz,1H), 3.83 (s, 3H), 3.74 (m, 2H), 3.55-3.35 (m, 4H), 2.41 (m, 2H), 2.15(m, 2H), 1.85-1.55 (m, 7H), 1.55-1.42 (m, 3H), 1.42-1.30 (m, 3H),1.30-1.10 (m, 2H), 1.08-0.80 (m, 5H).

EXAMPLE 6(3)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-allyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.46 (d, J=8.4Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.06 (m, 1H), 5.41 (m, 1H), 5.28 (m,2H), 4.59 (m, 2H), 4.28 (s, 2H), 4.04 (dd, J=7.2, 4.8 Hz, 1H), 3.77 (m,2H), 3.55-3.35 (m, 4H), 2.39 (m, 2H), 2.16 (m, 2H), 1.90-1.60 (m, 7H),1.60-1.45 (m, 2H), 1.45-1.30 (m, 2H), 1.30-1.10 (m, 3H), 1.10-0.80 (m,5H).

EXAMPLE 6(4)(3S)-1-propyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-2,5-dioxo-3-(2-methyl-1-propyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.65-7.45 (m,5H), 4.33 (s, 2H), 4.03 (dd, J=7.8, 5.2 Hz, 1H), 3.85 (m, 2H), 3.62 (m,2H), 3.44 (m, 2H), 2.59 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (m,2H), 1.81 (m, 1H), 1.71 (m, 2H), 1.64 (m, 2H), 1.00-0.90 (m, 9H).

EXAMPLE 6(5)(3R)-1-propyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-2,5-dioxo-3-(2-methyl-1-propyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.65-7.45 (m,5H), 4.33 (s, 2H), 4.03 (dd, J=7.8, 5.2 Hz, 1H), 3.85 (m, 2H), 3.62 (m,2H), 3.44 (m, 2H), 2.59 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (m,2H), 1.81 (m, 1H), 1.71 (m, 2H), 1.64 (m, 2H), 1.00-0.90 (m, 9H).

EXAMPLE 6(6)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-phenylmethyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.64-7.44 (m,5H), 4.36 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.77 (m, 2H), 3.55-3.35(m, 4H), 2.60-2.30 (m, 2H), 2.17 (m, 2H), 1.95-1.75 (m, 1H), 1.75-1.60(m, 2H), 1.60-1.45 (m, 2H), 1.45-1.20 (m, 2H), 1.10-0.80 (m, 9H).

EXAMPLE 6(7)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

TLC: Rf 0.41 (chloroform:methanol=20:1); NMR (CDCl₃): δ 7.45-7.28 (m,5H), 6.31 (m, 1H), 5.15 (s, 2H), 4.14 (m, 2H), 3.96 (m, 1H), 3.63 (m,1H), 3.44 (m, 1H), 3.26 (m, 2H), 1.99-1.14 (m, 11H), 1.02-0.88 (m, 9H).

EXAMPLE 6(8)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

TLC: Rf 0.46 (chloroform:methanol=20:1); NMR (CDCl₃): δ 7.40-7.29 (m,5H), 5.98 (m, 1H), 5.15 (s, 2H), 4.14 (m, 2H), 4.00 (m, 1H), 3.65 (m,1H), 3.43 (m, 1H), 3.26 (m, 2H), 2.03-1.81 (m, 4H), 1.80-1.60 (m, 5H),1.60-1.10 (m, 10H), 1.10-0.85 (m, 5H).

EXAMPLE 6(9)1-benzyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.66 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50 (d, J=8.4Hz, 2H), 7.45-7.12 (m, 8H), 7.10-6.98 (m, 4H), 4.82 (m, 2H), 4.29 (s,2H), 4.18 (dd, J=8.0, 4.6 Hz, 1H), 3.73 (m, 2H), 3.42 (m, 2H), 2.65-2.30(m, 2H), 2.20-2.05 (m, 2H), 2.00-1.60 (m, 3H), 0.98 (d, J=6.2 Hz, 6H).

EXAMPLE 6(10)1-butyl-2,5-dioxo-3-propyl-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10-7.00(m, 4H), 4.33 (s, 2H), 4.04 (dd, J=5.7, 4.5 Hz, 1H), 3.93-3.66 (m, 2H),3.55-3.31 (m, 4H), 2.47-2.09 (m, 4H), 1.92-1.68 (m, 2H), 1.61-1.21 (m,6H), 1.01-0.90 (m, 6H).

EXAMPLE 6(11)1-butyl-2,5-dioxo-3-methoxymethyl-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.2 Hz, 2H), 7.17 (t, J=7.2 Hz, 1H), 7.09-6.99(m, 4H), 4.30 (s, 2H), 4.07 (t, J=3.0 Hz, 1H), 3.91 (m, 1H), 3.77 (dd,J=9.0, 3.0 Hz, 1H), 3.67 (m, 1H), 3.58-3.39 (m, 4H), 3.31 (s, 3H), 3.26(m, 1H), 2.48-2.13 (m, 4H), 1.65 (m, 1H), 1.53-1.28 (m, 3H), 0.95 (t,J=7.5 Hz, 3H).

EXAMPLE 6(12)1-(1-methylpropyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.46 (d, J=8.4Hz, 2H), 7.38 (dd, J=8.4, 7.5 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H), 7.08-6.99(m, 4H), 4.15 (s, 2H), 3.91-3.82 (m, 1H), 3.81-3.65 (m, 1H), 3.64-3.44(m, 1H), 3.44-3.15 (m, 3H), 2.42-2.00 (m, 4H), 1.88-1.56 (m, 5H),1.46-1.37 (m, 3H), 0.99-0.85 (m, 9H).

EXAMPLE 6(13)1-(2-methylbutyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.49 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.2 Hz, 2H), 7.17 (t, J=7.2 Hz, 1H), 7.08-6.94(m, 4H), 4.27 (s, 2H), 4.04 (dd, J=8.4, 4.5 Hz, 1H), 3.83-3.21 (m, 6H),2.45-2.12 (m, 4H), 1.92-1.56 (m, 4H), 1.42 (m, 1H), 1.14 (m, 1H),1.00-0.83 (m, 12H).

EXAMPLE 6(14)1-(2-methylpropyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.17 (t, J=7.5 Hz, 1H), 7.13-7.04(m, 4H), 4.28 (s, 2H), 4.04 (dd, J=8.1, 4.2 Hz, 1H), 3.81-3.54 (m, 2H),3.52-3.21 (m, 4H), 2.46-2.11 (m, 4H), 2.00-1.57 (m, 4H), 0.94 (d, J=6.3Hz, 6H), 0.90 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.3 Hz, 3H).

EXAMPLE 6(15)1-(2-dimethylaminoethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.87 (chloroform:methanol:28% NH₄OH=80:10:1); NMR (CD₃OD): δ7.60 (d, J=8.7 Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.17 (t, J=7.5 Hz,1H), 7.07-6.99 (m, 4H), 4.33 (s, 2H), 4.07 (dd, J=8.4, 4.8 Hz, 1H),3.99-3.63 (m, 4H), 3.53-3.42 (m, 2H), 3.32-3.21 (m, 2H), 2.99 (s, 3H),2.96 (s, 3H), 2.70-2.49 (m, 2H), 2.30-2.10 (m, 2H), 1.93-1.56 (m, 3H),0.94 (d, J=6.6 Hz, 6H).

EXAMPLE 6(16)1-(2-methoxyethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.17 (t, J=7.5 Hz, 1H), 7.09-6.99(m, 4H), 4.25 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz, 1H), 3.75-3.34 (m, 8H),3.31 (s, 3H), 2.48-2.28 (m, 2H), 2.25-2.06 (m, 2H), 1.90-1.57 (m, 3H),0.94 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H).

EXAMPLE 6(17)1-(2-methylthioethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.48 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.8 Hz, 2H), 7.17 (t, J=7.8 Hz, 1H), 7.08-6.99(m, 4H), 4.25 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.81-3.49 (m, 4H),3.48-3.33 (m, 2H), 2.74-2.51 (m, 2H), 2.39-2.10 (m, 7H), 1.90-1.56 (m,3H), 0.94 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 6(18)1-benzyl-2,5-dioxo-3-(2-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.15 (m,5H), 7.03 (d, J=2.0 Hz, 1H), 6.96 (dd, J=8.2, 2.0 Hz, 1H), 6.90 (d,J=8.2 Hz, 1H), 4.80 (m, 2H), 4.25 (s, 4H), 4.21-4.10 (m, 3H), 3.80-3.55(m, 2H), 3.50-3.30 (m, 2H), 2.60-2.25 (m, 2H), 2.20-2.00 (m, 2H),2.00-1.60 (m, 3H), 0.98 (d, J=6.4 Hz, 6H).

EXAMPLE 6(19)1-benzyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-benzyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50-7.15 (m,12H), 7.07 (d, J=8.8 Hz, 2H), 5.12 (s, 2H), 4.81 (m, 2H), 4.24 (s, 2H),4.17 (dd, J=8.4, 4.8 Hz, 1H), 3.70-3.55 (m, 2H), 3.50-3.35 (m, 2H),2.60-2.25 (m, 2H), 2.20-2.00 (m, 2H), 2.00-1.60 (m, 3H), 0.98 (d, J=6.0Hz, 6H).

EXAMPLE 6(20)1-benzyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.70-7.45 (m,5H), 7.40-7.15 (m, 5H), 4.92 (m, 2H), 4.29 (s, 2H), 4.20 (dd, J=8.4, 4.8Hz, 1H), 3.90-3.65 (m, 2H), 3.65-3.45 (m, 2H), 2.85-2.50 (m, 2H), 2.44(s, 3H), 2.39 (s, 3H), 2.20-2.00 (m, 2H), 2.00-1.60 (m, 3H), 1.00 (d,J=5.4 Hz, 6H).

EXAMPLE 6(21)1-(3-methylphenylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.56 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.18 (t, J=7.8Hz, 1H), 7.10-6.85 (m, 6H), 4.77 (m, 2H), 4.25 (s, 4H), 4.19 (m, 3H),3.68 (m, 2H), 3.40 (m, 2H), 2.60-2.30 (m, 2H), 2.29 (s, 3H), 2.20-2.00(m, 2H), 2.00-1.60 (m, 3H), 0.99 (d, J=6.2 Hz, 6H).

EXAMPLE 6(22)1-(3-methylphenylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.70-7.45 (m,5H), 7.18 (t, J=7.4 Hz, 1H), 7.10-7.00 (m, 3H), 4.88 (s, 2H), 4.31 (s,2H), 4.20 (dd, J=8.2, 4.8 Hz, 1H), 3.76 (m, 2H), 3.60 (m, 2H), 2.90-2.50(m, 2H), 2.47 (s, 3H), 2.41 (s, 3H), 2.30 (s, 3H), 2.10 (m, 2H), 1.88(m, 1H), 1.85-1.65 (m, 2H), 1.00 (d, J=5.8 Hz, 6H).

EXAMPLE 6(23)1-(1-methylbutyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49, 0.56 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.49 (d,J=8.7 Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.17 (t, J=7.5 Hz, 1H),7.08-6.99 (m, 4H), 4.26 (s, 2H), 3.97-3.79 (m, 2H), 3.78-3.60 (m, 1H),3.54-3.33 (m, 3H), 2.47-2.29 (m, 2H), 2.26-2.03 (m, 3H), 1.87-1.71 (m,1H), 1.70-1.53 (m, 3H), 1.48-1.16 (m, 5H), 1.02-0.90 (m, 9H).

EXAMPLE 6(24)1-(3-methylbutyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10-7.00(m, 4H), 4.33 (s, 2H), 4.00 (dd, J=8.1, 4.8 Hz, 1H), 3.90-3.71 (m, 2H),3.56-3.34 (m, 4H), 2.46-2.29 (m, 2H), 2.28-2.10 (m, 2H), 1.90-1.56 (m,4H), 1.55-1.32 (m, 2H), 1.04-0.85 (m, 12H).

EXAMPLE 6(25)1-(2-methoxyphenylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-((3,5-dimethyl-phenyl)-4-pyrazolyl)methyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.38 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.59-7.41 (m,5H), 7.26-7.17 (m, 1H), 6.99-6.84 (m, 3H), 4.74 (brs, 2H), 4.27 (s, 2H),4.19 (dd, J=8.4, 4.5 Hz, 1H), 3.88 (s, 3H), 3.90-3.68 (m, 2H), 3.62-3.45(m, 2H), 2.60-2.14 (m, 4H), 2.35 (s, 3H), 2.33 (s, 3H), 2.00-1.63 (m,3H), 0.99 (d, J=6.3 Hz, 6H).

EXAMPLE 6(26)1-(3-methoxyphenylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-((3,5-dimethyl-1-phenyl)-4-pyrazolyl)methyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.33 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.65-7.48 (m,5H), 7.20 (t, J=8.1 Hz, 1H), 6.85-6.80 (m, 2H), 6.77 (dd, J=7.8, 2.1 Hz,1H), 4.90 (brs, 2H), 4.31 (s, 2H), 4.20 (dd, J=8.1, 4.8 Hz, 1H),3.84-3.65 (m, 2H), 3.75 (s, 3H), 3.65-3.48 (m, 2H), 2.84-2.56 (m, 2H),2.47 (s, 3H), 2.40 (s, 3H), 2.19-2.03 (m, 2H), 2.00-1.65 (m, 3H), 0.99(d, J=6.3 Hz, 6H).

EXAMPLE 6(27)1-(2-methylphenylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.35 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.63-7.46 (m,5H), 7.18-7.06 (m, 3H), 6.99-6.91 (m, 1H), 4.81 (brs, 2H), 4.29 (s, 2H),4.20 (dd, J=8.4, 4.5 Hz, 1H), 3.90-3.66 (m, 2H), 3.63-3.57 (m, 2H),2.75-2.40 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 2.30-2.10(m, 2H), 2.00-1.65 (m, 3H), 0.99 (d, J=6.3 Hz, 6H).

EXAMPLE 6(28)1-(3-methylphenylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.53-7.46 (m,2H), 7.42-7.36 (m, 2H), 7.22-7.14 (m, 2H), 7.06-6.96 (m, 7H), 4.85-4.65(m, 2H), 4.28 (s, 2H), 4.18 (dd, J=8.1, 4.5 Hz, 1H), 3.80-3.62 (m, 2H),3.50-3.30 (m, 2H), 2.58-2.25 (m, 2H), 2.29 (s, 3H), 2.18-2.04 (m, 2H),1.95-1.62 (m, 3H), 0.98 (d, J=6.3 Hz, 6H). EXAMPLE 6(29)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(5-ethylthiophen-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.62 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.17 (d, J=3.6Hz, 1H), 6.85 (d, J=3.6 Hz, 1H), 4.53 (s, 2H), 4.04 (dd, J=7.8, 4.5 Hz,1H), 3.88-3.72 (m, 2H), 3.58-3.45 (m, 2H), 3.43-3.33 (m, 2H), 2.87 (q,J=7.5 Hz, 2H), 2.50-2.30 (m, 2H), 2.30-2.08 (m, 2H), 1.83-1.10 (m, 17H),1.31 (t, J=7.5 Hz, 3H), 1.05-0.85 (m, 2H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 6(30)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(5-ethylfuran-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.62 (chloroform:methanol=20:1); NMR (CD₃OD): δ 6.63 (d, J=3.0Hz, 1H), 6.14 (d, J=3.0 Hz, 1H), 4.39 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz,1H), 3.90-3.70 (m, 2H), 3.55-3.40 (m, 2H), 3.40-3.35 (m, 2H), 2.69 (q,J=7.5 Hz, 2H), 2.50-2.30 (m, 2H), 2.30-2.10 (m, 2H), 1.85-1.05 (m, 17H),1.25 (t, J=7.5 Hz, 3H), 1.05-0.85 (m, 2H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 6(31)(3S)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=9.0Hz, 2H), 7.44-7.35 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10-7.00 (m, 4H),4.33(s, 2H), 4.16-4.00 (m, 2H), 3.75-3.40 (m, 5H), 3.26-3.09 (m, 1H),2.56-2.08 (m, 4H), 1.82-1.60 (m, 2H), 1.50-1.30 (m, 3H), 1.05-0.89 (m,9H).

EXAMPLE 6(32)(3R)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=9.0Hz, 2H), 7.44-7.35 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10-7.00 (m, 4H),4.33(s, 2H), 4.16-4.00 (m, 2H), 3.75-3.40 (m, 5H), 3.26-3.09 (m, 1H),2.56-2.08 (m, 4H), 1.82-1.60 (m, 2H), 1.50-1.30 (m, 3H), 1.05-0.89 (m,9H).

EXAMPLE 7(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-allyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Reference Example 9→ReferenceExample 10→Example 1 using Resin (6) prepared in Reference Example 8,N-allyloxycarbonyl-4-piperidone, n-propylamine andN-(t-butyloxycarbonyl)-N′-(benzyloxycarbonyl)-L-lysine, the compound ofthe present invention having the following physical data was obtained.

TLC: Rf 0.24 (ethyl acetate:hexane=4:1); NMR (CD₃OD): δ 7.35 (m, 5H),6.40 (m, 1H), 5.96 (ddt, J=17.2, 10.2, 5.6 Hz, 1H), 5.34 (m, 1H), 5.24(m, 1H), 5.12 (s, 2H), 4.88 (m, 1H), 4.62 (m, 2H), 4.10 (m, 2H), 4.00(m, 1H), 3.75 (m, 1H), 3.36 (m, 2H), 3.18 (m, 3H), 1.94 (m, 6H), 1.51(m, 6H), 0.90 (t, J=7.2 Hz, 3H).

EXAMPLE 8(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Reference Example 4 using thecompound prepared in Example 7, and furthermore, purification bycation-exchange resin and column chromatography on silica gel, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.56 (chloroform:methanol:28% NH₄OH=20:5:1); NMR (CD₃OD): δ7.40-7.20 (m, 10H), 5.06 (s, 2H), 4.03 (t, J=5.0 Hz, 1H), 3.55-3.18 (m,4H), 3.12 (t, J=6.6 Hz, 2H), 3.08-2.98 (m, 2H), 2.20-1.70 (m, 6H),1.70-1.20 (m, 6H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 8(1)1-propyl-2,5-dioxo-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 7→Example 8 usingN-(t-butyloxycarbonyl)leucine instead ofN-(t-butyloxycarbonyl)-N′-(benzyloxycarbonyl)-L-lysine, the compound ofthe present invention having the following physical data was obtained.

TLC: Rf 0.44 (chloroform:methanol:triethylamine=18:2:1); NMR (CD₃OD): δ3.99 (d, J=7.8, 4.4 Hz, 1H), 3.50-3.20 (m, 4H), 3.05-2.85 (m, 2H),2.10-1.75 (m, 5H), 1.75-1.40 (m, 4H), 1.00-0.85 (m, 9H).

EXAMPLE 91-butyl-2,5-dioxo-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Example 6(7) (202 mg) inmethanol (5 ml) was added 5% palladium on carbon (20 mg). Under anatmosphere of hydrogen, the reaction mixture was stirred for 3 hours atroom temperature. The reaction mixture was filtrated through Celite(brand name). The filtrate was concentrated to give the compound of thepresent invention (127 mg) having the following physical data.

TLC: Rf 0.61 (chloroform:methanol:28% NH₄OH=20:5:1); NMR (CD₃OD): δ 3.97(dd, J=7.8 Hz, 4.5 Hz, 1H), 3.48-3.22 (m, 4H), 3.00-2.90 (m, 2H),2.12-1.60 (m, 11H), 0.95 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.93(d, J=6.6 Hz, 3H).

EXAMPLE 9(1)1-butyl-2,5-dioxo-3-cyclohexylmethyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 9 using the compoundprepared in Example 6(8) instead of the compound prepared in Example6(7), the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.65 (chloroform:methanol:28% NH₄OH=20:5:1); NMR (CD₃OD): δ 4.00(dd, J=7.8 Hz, 4.5 Hz, 1H), 3.46-3.24 (m, 4H), 3.03-2.92 (m, 2H),2.08-1.08 (m, 19H), 1.05-0.84 (m, 5H).

EXAMPLE 10(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(4-dihydroxyboranephenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

The compound prepared in Example 8 (70 mg) was dissolved in 1% aceticacid-dimethylformamide solution (2 ml). To this solution were addedsodium triacetoxyborohydride (46 mg) and 4-formylphenylboronic acid (30mg). The reaction mixture was stirred for 46 hours at room temperature.To the reaction mixture was added 10% acetic acid-methanol solution.This solution was loaded on cation-exchange resin (BondElut-SCX, VarianCo. Ltd., 0.6 mmol/g, 500 mg/3 ml), and the resin was washed withmethanol, and furthermore, was eluted with 10% triethylamine-methanolsolution. Only solution which was eluted with 10% triethylamine-methanolsolution, was concentrated. The obtained residue was purified by columnchromatography on silica gel (chloroform:methanol=1:0→30:1→10:1) to givethe compound of the present invention (45 mg) having the followingphysical data.

TLC: Rf 0.24 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.73 (br, 2H),7.52 (br, 2H), 7.32 (m, 5H), 5.03 (s, 2H), 4.36 (s, 2H), 4.05 (t, J=4.8Hz, 1H), 3.81 (m, 2H), 3.46 (m, 3H), 3.10 (t, J=6.6 Hz, 2H), 2.37 (br,2H), 2.22 (br, 2H), 1.92-1.66 (m, 2H), 1.60-1.28 (m, 7H), 0.91 (t, J=7.5Hz, 3H).

EXAMPLE 10(1)(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(1,3-benzodioxalan-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 10 using2,3-(methylenedioxy)benzaldehyde instead of 4-formylphenylboronic acid,the compound of the present invention having the following physical datawas obtained.

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.32 (m, 5H),6.96 (m, 3H), 6.05 (s, 2H), 5.04 (s, 2H), 4.33 (s, 2H), 4.05 (t, J=4.5Hz, 1H), 3.98-3.54 (m, 2H), 3.53 (m, 2H), 3.38 (m, 3H), 3.11 (t, J=6.6Hz, 2H), 2.37 (br, 2H), 2.22 (br, 2H), 1.98-1.76 (m, 2H), 1.61-1.28 (m,5H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 111-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(1-(1,4-benzodioxan-6-yl)ethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

Under an atmosphere of argon, to a solution of the compound prepared inExample 9 (315 mg) in dichloromethane (5 ml) were added1,4-benzodioxan-6-yl methyl ketone (285 mg), triethylamine (0.354 ml)and a solution of titanium tetrachloride in dichloromethane (1.0 M, 0.63ml). The reaction mixture was stirred for 16 hours at room temperature.To the reaction mixture was added a solution of sodium cyanoborohydride(133 mg) in methanol (2 ml). The reaction mixture was stirred for 1 hourat room temperature. To the reaction mixture was added 2N aqueoussolution of sodium hydroxide, and was extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was purified by column chromatography on silica gel(Fuji Silysia Chemical Ltd., BW235; chloroform:methanol=50:1). Theobtained residue was dissolved in methanol. The solution was acidifiedby adding 1N hydrochloric acid, and was concentrated to give thecompound of the present invention (176 mg) having the following physicaldata.

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.1Hz, 1H), 6.98 (dd, J=8.4, 2.1 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.40 (q,J=6.9 Hz, 1H), 4.26 (s, 4H), 3.98 (dd, J=8.1, 4.5 Hz, 1H), 3.82-3.17 (m,6H), 2.55-2.04 (m, 4H), 1.87-1.28 (m, 10H), 1.04-0.85 (m, 9H).

EXAMPLE 11(1)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(1-(4-phenyloxyphenyl)ethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 11 using4-phenoxyacetophenone instead of 1,4-benzodioxan-6-yl methyl ketone, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.58, 0.62 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d,J=8.7 Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.17 (t, J=7.5 Hz, 1H),7.09-7.01 (m, 4H), 4.48 (m, 1H), 3.98 (dd, J=7.8, 4.8 Hz, 1H), 3.80-3.17(m, 6H), 2.56-2.28 (m, 2H), 2.28-2.03 (m, 2H), 1.88-1.24 (m, 7H), 1.76(d, J=6.9 Hz, 3H), 1.04-0.86 (m, 9H).

EXAMPLE 121-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(1-(1,4-benzodioxan-6-yl)ethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 11 using the compoundprepared in Example 9(1) instead of the compound prepared in Example 9,the compound of the present invention having the following physical datawas obtained.

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.02 (d, J=1.8Hz, 1H), 6.96 (dd, J=8.4, 1.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.39 (m,1H), 4.26 (s, 4H), 4.01 (dd, J=7.5, 4.5 Hz, 1H), 3.80-3.20 (m, 6H),2.50-2.02 (m, 4H), 1.82-1.13 (m, 18H), 1.04-0.83 (m, 5H).

EXAMPLE 13(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-allyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

Under an atmosphere of argon, to a solution of the compound prepared inExample 7 (225 mg) in tetrahydrofuran (5 ml) was addedtetrakis(triphenylphosphine)palladium (0) (51 mg) at room temperature.The reaction mixture was stirred for 16 hours at room temperature. Thereaction mixture was loaded on cation-exchange resin (BondElut-SCX,Varian Co. Ltd., 0.6 mmol/g, 500 mg/3 ml), and the resin was washed withmethanol, and furthermore, was eluted with 10% triethylamine-methanolsolution (20 ml). Only solution which was eluted with 10%triethylamine-methanol solution, was concentrated. The obtained residuewas purified by column chromatography on silica gel(chloroform:methanol=20:1) to give the compound of the present invention(122 mg) having the following physical data.

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.34 (m, 5H),6.00 (m, 1H), 5.62 (m, 1H), 5.61 (m, 1H), 5.06 (s, 2H), 4.07 (t, J=5.2Hz, 1H), 3.77 (m, 4H), 3.44 (m, 4H), 3.12 (t, J=6.6 Hz, 2H), 2.39 (m,2H), 2.20 (m, 2H), 1.84 (m, 2H), 1.54 (m, 4H), 1.37 (m, 2H), 0.94 (t,J=7.2 Hz, 3H).

EXAMPLE 14(3S)-1-propyl-2,5-dioxo-3-(4-aminobutyl)-9-phenylethyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 9 using the compoundprepared in Example 5(11) instead of the compound prepared in Example6(7), the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.66 (chloroform:methanol:28% NH₄OH=20:5:1); NMR (CD₃OD): δ 7.23(m, 5H), 4.05 (t, J=5.2 Hz, 1H), 3.42 (m, 2H), 2.98 (m, 3H), 2.81 (m,3H), 2.65 (m, 4H), 2.16 (m, 2H), 1.99 (m, 1H), 1.89 (m, 3H), 1.53 (m,3H), 1.48 (m, 3H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 15(3S)-1-propyl-2,5-dioxo-3-(4-(N-(4-phenyl)phenylcarbonyl)aminobutyl)-9-phenylethyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

To a solution of the compound prepared in Example 14 (42 mg) indichloroethane (2 ml) were added diisopropylethylamine (35 μl) and4-phenylbenzoyl chloride (33 mg). The reaction mixture was stirred for 3hours at room temperature. The reaction mixture was loaded oncation-exchange resin (BondElut-SCX, Varian Co. Ltd., 0.6 mmol/g, 500mg/3 ml), and the resin was washed with methanol, and furthermore, waseluted with 10% triethylamine-methanol solution (20 ml). Only solutionwhich was eluted with 10% triethylamine-methanol solution, wasconcentrated. The obtained residue was purified by column chromatographyon silica gel (chloroform:methanol=10:0→10:1). To the obtained compoundwas added 4N hydrogen chloride-ethyl acetate solution to give thecompound of the present invention (66 mg) having the following physicaldata.

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.89 (d, J=8.1Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.65 (d, J=7.2 Hz, 2H), 7.45 (t, J=7.2Hz, 2H), 7.39-7.26 (m, 6H), 4.11 (m, 1H), 3.86-3.71 (m, 2H), 3.63-3.53(m, 2H), 3.45-3.30 (m, 4H), 3.07 (m, 2H), 2.42 (br, 2H), 2.19 (m, 2H),1.99-1.78 (m, 2H), 1.68-1.28 (m, 7H), 0.86 (t, J=7.5 Hz, 3H).

EXAMPLE 161-butyl-2,5-dioxo-3-cyclohexylmethyl-9-methyl-9-(1-(1,4-benzodioxan-6-yl)ethyl)-1,4,-diaza-9-azoniaspiro[5.5]undecaneiodide

To a solution of the compound prepared in Example 2(1) (50 mg) inchloroform (2 ml) was added 1N aqueous solution of sodium hydroxide (2ml). The reaction mixture was stirred for 10 minutes at roomtemperature. The aqueous layer of the reaction mixture was removed. Theorganic layer was washed with water, dried over anhydrous magnesiumsulfate and concentrated. To a solution of the obtained residue inacetone (2 ml) was added methyl iodide (118 μl). The reaction mixturewas stirred for 18 hours at room temperature. The reaction mixture wasconcentrated. The obtained residue was solidified by diethyl ether togive the compound of the present invention (58 mg) having the followingphysical data.

TLC: Rf 0.23(ethyl acetate:acetic acid:water=8:1:1); NMR (CD₃OD): δ7.10-6.90 (m, 3H), 4.60+4.49 (s+s, 2H), 4.29 (s, 4H), 4.20-4.00 (m, 3H),3.70-3.35 (m, 4H), 3.11+2.99 (s+s, 3H), 2.80-2.30 (m, 2H), 2.30-2.00 (m,2H), 1.90-1.10 (m, 15H), 1.10-0.80 (m, 5H).

EXAMPLE 17(3S)-3-(4-(N-benzyloxycarbonyl)aminobutyl)-2,5-dioxo-9-(2-hydroxy-2-phenylethyl)-1-propyl-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Example 8 (0.01 g) in2-propanol (0.4 ml) was added styrene oxide (10 μl). The reactionmixture was refluxed for 4 hours. The reaction mixture was cooled toroom temperature, and was loaded on ion exchange resin (OASIS MCX,Waters, 60 mg) washed with methanol (3 ml) prior to use. The resin waswashed with methanol (2 ml), and was eluted with 10%triethylamine-methanol solution (2 ml). The elution was concentrated togive the compound of the present invention (13 mg) having the followingphysical data.

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.20 (m,10H), 5.06 (s, 2H), 4.03 (m, 1H), 3.40 (m, 2H), 3.12 (m, 2H), 3.10-2.60(m, 6H), 2.50 (m, 1H), 2.40-2.00 (m, 2H), 2.00-1.70 (m, 4H), 1.70-1.20(m, 6H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 18(3S)-3-(4-(N-benzyloxycarbonyl)aminobutyl)-2,5-dioxo-9-(2-oxo2-phenylethyl)-1-propyl-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Example 8 (0.01 g) indimethylformamide (0.4 ml) were added triethylamine (6 μl), and phenacylbromide (9 mg). The reaction mixture was allowed to stand for 24 hoursat room temperature. The reaction mixture was acidified by adding aceticacid (0.4 ml). The reaction mixture was loaded on ion exchange resin(OASIS MCX, Waters, 120 mg) washed with methanol (6 ml) prior to use.The resin was washed with methanol (2 ml), and was eluted with 10%triethylamine-methanol solution (4 ml). The elution was concentrated togive the compound of the present invention (12 mg) having the followingphysical data.

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.01 (m, 2H),7.54 (m, 3H), 7.33 (m, 5H), 5.05 (s, 2H), 4.02 (m, 1H), 4.00 (s, 2H),3.44 (m, 2H), 3.12 (t, J=6.6 Hz, 2H), 2.95 (m, 2H), 2.40-2.10 (m, 2H),2.00-1.70 (m, 5H), 1.68-1.20 (m, 7H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 19(3S)-1-(2-methylpropyl)-2,5-dioxo-3-methyl-9-allyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

To a suspension of Resin (6) prepared in Reference Example 8 (300 mg) intetrahydrofuran (1.5 ml) and methanol (1.5 ml) were addedN-allyloxycarbonyl-4-piperidone (403 mg), isobutylamine (0.22 ml) andN-(t-butyloxycarbonyl)-L-alanine (381 mg) at room temperature. Thereaction mixture was stirred for 20 hours at 65° C. The reaction mixturewas cooled to room temperature and the resin was collected byfiltration. The obtained resin was washed with tetrahydrofuran (3 ml×4)and dichloromethane (3 ml×5), and dried. The resin (384 mg) wasobtained. To a suspension of the obtained resin (146 mg) in 1.5 M2,6-lutidine-dichloromethane (2 ml) was added 1M trimethylsilyltrifluoromethanesulfonate-dichloromethane solution (2 ml). It wasstirred for 30 minutes at room temperature. The reaction mixture wasfiltrated, and the resin was washed with dichloromethane (2 ml×3). Theobtained resin was suspended in 1.5 M 2,6-lutidine-dichloromethanesolution (2 ml) and 1M trimethylsilyltrifluoromethanesulfonate-dichloromethane solution (2 ml) was addedthereto. The reaction mixture was stirred for 30 minutes at roomtemperature. The resin was collected by filtration from the reactionsolution, and was washed with dichloromethane (2 ml×4), methanol (2ml×4) and dichloromethane (2 ml×4), dried and the resin was obtained.The obtained resin was suspended in 1.25M acetic acid-toluene solution(2 ml). The reaction mixture was stirred for 20 hours at 90° C. Thereaction mixture was filtrated, and the resin was washed with toluene (2ml×3) and methanol (2 ml×4). The filtrate was concentrated to give thecompound of the present invention (19 mg) having the following physicaldata.

TLC: Rf 0.39 (chloroform:methanol=10:1); MS (ESI, Pos., 20 V): 388(M+H)⁺; HPLC condition: F; HPLC retention time: 3.40 min; NMR (CD₃OD): δ5.98 (ddt, J=15.8, 10.4, 5.4 Hz, 1H), 5.30 (m, 1H), 5.21 (m, 1H), 4.59(m, 2H), 4.20-4.00 (m, 3H), 3.85-3.60 (m, 2H), 3.41 (dd, J=14.2, 8.0 Hz,1H), 3.18 (dd, J=14.2, 7.2 Hz, 1H), 2.10-1.70 (m, 5H), 1.43 (d, J=6.8Hz, 3H), 0.89 (t, J=6.2 Hz, 6H).

EXAMPLE 19(1)(3S)-1-(2-methylpropyl)-2,5-dioxo-3-methyl-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.acetate

By the same procedure as described in Example 19 using Resin (6)prepared in Reference Example 8 (200 mg), N-(2-phenylethyl)-4-piperidone(252 mg), isobutylamine (0.123 ml) and N-(t-butyloxycarbonyl)-L-alanine(235 mg), the compound of the present invention (50 mg) having thefollowing physical data was obtained.

TLC: Rf 0.46 (chloroform:methanol=10:1); MS (ESI, Pos., 20 V): 358(M+H)⁺; HPLC condition: F; HPLC retention time: 3.14 min; NMR (CD₃OD): δ7.40-7.20 (m, 5H), 4.15 (q, J=6.8 Hz, 1H), 3.65 (m, 1H), 3.55-3.35 (m,3H), 3.25-3.05 (m, 3H), 3.05-2.90 (m, 3H), 2.50-2.05 (m, 4H), 1.98 (s,3H), 1.92 (m, 1H), 1.43 (d, J=6.8 Hz, 3H), 0.92 (t, J=6.4 Hz, 6H).

EXAMPLE 19(2)(3S)-1-(2-methylpropyl)-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.acetate

By the same procedure as described in Example 19 using Resin (6)prepared in Reference Example 8 (200 mg), N-(2-phenylethyl)-4-piperidone(252 mg), isobutylamine (0.123 ml) andN-(t-butyloxycarbonyl)-N′-(benzyloxycarbonyl)-L-lysine (472 mg), thecompound of the present invention (71 mg) having the following physicaldata was obtained.

TLC: Rf 0.44 (chloroform:methanol=10:1); MS (ESI, Pos., 20 V): 549(M+H)⁺; HPLC condition: F; HPLC retention time: 3.49 min; NMR (CD₃OD): δ7.40-7.20 (m, 10H), 5.06 (s, 2H), 4.10 (m, 1H), 3.67 (m, 1H), 3.60-3.40(m, 3H), 3.28-3.05 (m, 5H), 3.05-2.90 (m, 3H), 2.50-2.10 (m, 4H), 1.98(s, 3H), 2.05-1.70 (m, 3H), 1.65-1.20 (m, 4H), 0.92 (t, J=6.2 Hz, 6H).

EXAMPLE 19(3)(3S)-1-(1-benzylpiperidin-4-yl)-2,5-dioxo-3-methyl-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.2acetate

By the same procedure as described in Example 19 using Resin (6)prepared in Reference Example 8 (200 mg), N-(2-phenylethyl)-4-piperidone(252 mg), 4-amino-1-benzylpiperidine (0.253 ml) andN-(t-butyloxycarbonyl)-L-alanine (235 mg), the compound of the presentinvention (41 mg) having the following physical data was obtained.

TLC: Rf 0.10 (chloroform:methanol=10:1); MS (ESI, Pos., 20 V): 475(M+H)⁺; HPLC condition: F; HPLC retention time: 3.09 min; NMR (CD₃OD): δ7.47 (m, 5H), 7.40-7.20 (m, 5H), 4.19 (s, 2H), 4.00 (q, J=6.8 Hz, 1H),3.80-3.53 (m, 4H), 3.53-3,35 (m, 4H), 3.30-3.15 (m, 2H), 3.15-2.90 (m,3H), 2.55-2.30 (m, 3H), 2.30-2.00 (m, 2H), 1.98 (s, 6H), 1.85-1.70 (m,3H), 1.42 (d, J=7.0 Hz, 3H).

EXAMPLE 19(4)(3S)-1-(1-benzylpiperidin-4-yl)-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.2acetate

By the same procedure as described in Example 19 using Resin (6)prepared in Reference Example 8 (200 mg), N-(2-phenylethyl)-4-piperidone(252 mg), 4-amino-1-benzylpiperidine (0.253 ml) andN-(t-butyloxycarbonyl)-N′-(benzyloxycarbonyl)-L-lysine (472 mg), thecompound of the present invention (33 mg) having the following physicaldata was obtained.

TLC: Rf 0.12 (chloroform:methanol=10:1); MS (ESI, Pos., 20 V): 666(M+H)⁺; HPLC condition: F; HPLC retention time: 3.36 min; NMR (CD₃OD): δ7.46 (m, 5H), 7.40-7.20 (m, 10H), 5.03 (s, 2H), 4.19 (s, 2H), 3.99 (m,1H), 3.80-3.40 (m, 6H), 3.30-2.85 (m, 9H), 2.50-2.10 (m, 6H), 1.98 (s,6H), 1.95-1.60 (m, 4H), 1.60-1.40 (m, 4H).

EXAMPLE 19(5)(3S)-1-(2,2-diphenylpropyl)-2,5-dioxo-3-methyl-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.acetate

By the same procedure as described in Example 19 using Resin (6)prepared in Reference Example 8 (200 mg), N-(2-phenylethyl)-4-piperidone(252 mg), 2,2-diphenylpropylamine (307 mg) andN-(t-butyloxycarbonyl)-L-alanine (235 mg), the compound of the presentinvention (22 mg) having the following physical data was obtained.

TLC: Rf 0.42 (chloroform:methanol=10:1); MS (ESI, Pos., 20 V): 496(M+H)⁺; HPLC condition: F; HPLC retention time: 3.58 min; NMR (CD₃OD): δ7.40-7.10 (m, 15H), 4.79 (m, 1H), 4.16 (m, 1H), 3.93 (m, 1H), 3.71 (s,2H), 3.23 (m, 1H), 3.10-2.80 (m, 5H), 1.98 (s, 3H), 1.95-1.82 (m, 2H),1.70-1.15 (m, 1H), 1.58 (s, 3H), 1.49 (d, J=6.8 Hz, 3H), 0.70 (m, 1H).

EXAMPLE 19(6)(3S)-1-(2,2-diphenylpropyl)-2,5-dioxo-3-(4-(N-benzyloxycarbonyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.acetate

By the same procedure as described in Example 19 using Resin (6)prepared in Reference Example 8 (200 mg), N-(2-phenylethyl)-4-piperidone(252 mg), 2,2-diphenylpropylamine (307 mg) andN-(t-butyloxycarbonyl)-N′-(benzyloxycarbonyl)-L-lysine (472 mg), thecompound of the present invention (18 mg) having the following physicaldata was obtained.

MS (ESI, Pos., 20 V): 687 (M+H)⁺; HPLC condition: F; HPLC retentiontime: 3.80 min;

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.00 (m,20H), 5.06 (s, 2.H), 4.16 (m, 1H), 3.93 (m, 1H), 3.70 (s, 2H), 3.55 (m,1H), 3.30-3.10 (m, 2H), 3.10-2.80 (m, 6H), 1.98 (s, 3H), 1.95-1.85 (m,2H), 1.80 (s, 3H), 1.70-1.30 (m, 8H).

EXAMPLE 19(7)(3S)-1-propyl-2,5-dioxo-3-(4-benzyloxyphenylmethyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.acetate

By the same procedure as described in Example 19 using Resin (6)prepared in Reference Example 8 (0.5 g), N-(2-phenylethyl)-4-piperidone(0.32 g), n-propylamine (0.13 ml) andN-(t-butyloxycarbonyl)-O-benzyl-L-tyrosine (0.58 g), the compound of thepresent invention (68 mg) having the following physical data wasobtained.

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50-7.10 (m,10H), 7.06 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 4.31(m, 1H), 3.68 (m, 1H), 3.40 (m, 1H), 3.28-3.13 (m, 4H), 3.13-2.80 (m,6H), 2.30-2.00 (m, 2H), 1.80-1.35 (m, 4H), 0.91 (t, J=7.2 Hz, 3H).

EXAMPLE 20(3S)-1-propyl-2,5-dioxo-3-(4-(benzylcarbonylamino)butyl)-9-(2,4,6-trimethoxybenzyl)-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Example 8 (0.01 g) indichloroethane (0.2 ml) were added 2,4,6-trimethoxybenzaldehyde (0.013g), sodium triacetoxyborohydride (0.015 g) and dimethylformamide (0.2ml). The reaction mixture was stirred for 50 hours at room temperature.The reaction mixture was loaded on ion exchange resin (OASIS MCX,Waters, 60 mg) washed with methanol (3 ml) prior to use. The resin waswashed with methanol (2 ml), and was eluted with 10%triethylamine-methanol solution (2 ml). The elution was concentrated togive the compound of the present invention (4.4 mg) having the followingphysical data.

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 5H),6.21 (s, 2H), 5.05 (s, 2H), 4.00 (m, 1H), 3.80 (s, 9H), 3.59 (s, 2H),3.40 (m, 2H), 3.11 (t, J=6.6 Hz, 2H), 3.05-2.75 (m, 4H), 2.40-2.00 (m,2H), 2.00-1.70 (m, 4H), 1.65-1.25 (m, 6H), 0.90 (t, J=7.2 Hz, 3H).

EXAMPLE 20(1)(3S)-1-propyl-2,5-dioxo-3-(4-(benzylcarbonylamino)butyl)-9-(2,2-dimethylpropyl)-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 20 using the compoundprepared in Example 8 (0.01 g) and pivalaldehyde (8 μl), the compound ofthe present invention (2.5 mg) having the following physical data wasobtained.

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.33 (m, 5H),5.06 (s, 2H), 4.02 (m, 1H), 3.50-3.30 (m, 2H), 3.20-3.00 (m, 4H),3.00-2.60 (m, 4H), 2.20-2.00 (m, 2H), 1.90-1.70 (m, 3H), 1.70-1.20 (m,7H), 0.92 (t, J=7.4 Hz, 3H), 0.90 (s, 9H).

EXAMPLE 21(3S)-1-propyl-2,5-dioxo-3-(4-(benzylcarbonylamino)butyl)-9-(3-phenylpropanoyl)-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Example 8 (0.01 g) indichloroethane (0.2 ml) were added diisopropylethylamine (6 μl),3-phenylpropanoyl chloride (5 μl). The reaction mixture was stirred for1 hour at room temperature. The reaction mixture was passed through thecolumn with aminomethylated polystyrene-2% divinylbenzene copolymerresin (NovaBiochem, AM Resin, 50 mg). The resin was washed withdichloroethane and filtrated. The filtrate was concentrated to give thecompound of the present invention (14 mg) having the following physicaldata.

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.10 (m,10H), 5.06 (s, 2H), 4.03 (m, 1H), 3.70-3.55 (m, 2H), 3.28-3.00 (m, 5H),3.00-2.80 (m, 3H), 2.80-2.60 (m, 2H), 2.00-1.65 (m, 6H), 1.65-1.40 (m,6H), 0.90 (t, J=7.2 Hz, 3H).

EXAMPLE 21(1)(3S)-1-propyl-2,5-dioxo-3-(4-(benzylcarbonylamino)butyl)-9-benzenesulfonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 21 using the compoundprepared in Example 8 (0.01 g), diisopropylethylamine (6 μl) andbenzenesulfonyl chloride (4.5 μl), the compound of the present invention(16 mg) having the following physical data was obtained.

TLC: Rf 0.58 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.80 (m, 2H),7.63 (m, 3H), 7.33 (m, 5H), 5.04 (s, 2H), 3.98 (t, J=4.8 Hz, 1H),3.60-3.35 (m, 2H), 3.28-2.90 (m, 6H), 2.20-1.65 (m, 6H), 1.65-1.20 (m,6H), 0.89 (t, J=7.2 Hz, 3H).

EXAMPLE 21(2)(3S)-1-propyl-2,5-dioxo-3-(4-(benzylcarbonylamino)butyl)-9-benzylaminocarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 21 using the compoundprepared in Example 8 (0.01 g) and benzyl isocyanate (4 μl), thecompound of the present invention (16 mg) having the following physicaldata was obtained.

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.10 (m,10H), 5.05 (s, 2H), 4.37 (s, 2H), 4.10-3.90 (m, 3H), 3.60-3.45 (m, 2H),3.30-3.00 (m, 4H), 2.10-1.70 (m, 6H), 1.65-1.20 (m, 6H), 0.87 (t, J=7.4Hz, 3H).

EXAMPLE 22(3S)-1-propyl-2,5-dioxo-3-(4-(3-phenylpropanoyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Example 14 (5 mg) indichloroethane (0.5 ml) were added pyridine (2 μl), 3-phenylpropanoylchloride (4 μl). The reaction mixture was stirred for 3 hours at roomtemperature. To the reaction mixture was added methanol, and it wasloaded on ion exchange resin (OASIS MCX, Waters, 60 mg) washed withmethanol (3 ml) prior to use. The resin was washed with methanol (2 ml),and was eluted with 10% triethylamine-methanol solution (2 ml). Theelution was concentrated to give the compound of the present invention(1.6 mg) having the following physical data.

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.10 (m,10H), 4.03 (m, 1H), 3.60-3.30 (m, 2H), 3.14 (m, 2H), 3.06-2.90 (m, 3H),2.90-2.75 (m, 4H), 2.75-2.60 (m, 3H), 2.45 (t, J=7.4 Hz, 2H), 2.30-2.00(m, 2H), 2.00-1.70 (m, 4H), 1.70-1.20 (m, 6H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 22(1)(3S)-1-propyl-2,5-dioxo-3-(4-benzenesulfonylaminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 22 using the compoundprepared in Example 14 (5 mg), pyridine (2 μl), benzenesulfonyl chloride(3 μl), the compound of the present invention (4.4 mg) having thefollowing physical data was obtained.

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.84 (m, 2H),7.59 (m, 3H), 7.34-7.10 (m, 5H), 4.01 (t, J=5.0 Hz, 1H), 3.55-3.30 (m,2H), 3.05-2.90 (m, 3H), 2.90-2.75 (m, 4H), 2.75-2.60 (m, 3H), 2.30-2.00(m, 2H), 1.96 (m, 2H), 1.88-1.70 (m, 2H), 1.70-1.20 (m, 6H), 0.94 (t,J=7.4 Hz, 3H).

EXAMPLE 22(2)(3S)-1-propyl-2,5-dioxo-3-(4-(N-benzylcarbamoyl)aminobutyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 22 using the compoundprepared in Example 14 (5 mg), and benzyl isocyanate (3 μl), thecompound of the present invention (7 mg) having the following physicaldata was obtained.

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.10 (m,10H), 4.30 (s, 2H), 4.04 (t, J=5.0 Hz, 1H), 3.55-3.30 (m, 2H), 3.15 (t,J=6.6 Hz, 3H), 3.05-2.90 (m, 3H), 2.90-2.75 (m, 3H), 2.75-2.60 (m, 2H),2.35-2.05 (m, 2H), 2.02-1.70 (m, 4H), 1.70-1.20 (m, 6H), 0.93 (t, J=7.4Hz, 3H).

EXAMPLE 231-cyclopropylmethyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenoxyphenyl)-1,3,9-triazaspiro[5.5]undecane.acetate

To a suspension of Resin (3) prepared in Reference Example 2 (0.5 g) intetrahydrofuran/methanol (1:1; 5 ml) were addedN-allyloxycarbonyl-4-piperidone (0.396 g), cyclopropylmethylamine (0.189ml) and N-(t-butyloxycarbonyl)leucine (0.542 g), and it was stirred for18 hours at 65° C. The reaction solution was cooled to room temperatureand the resin was collected by filtration. The obtained resin was washedwith dimethylformamide (5 ml×2), dichloromethane (5 ml×2), methanol (5ml×2) and dichloromethane (5 ml×2). To a suspension of the obtainedresin in dichloromethane (5 ml) were added acetic acid (0.149 ml),tributyltin hydride (0.351 ml) and tetrakis(triphenylphosphine)palladium(0) complex (50 mg), and it was stirred for 6 hours at room temperature.The resin was collected by filtration from the reaction solution, andwas washed with dichloromethane (5 ml×4) and dimethylformamide (5 ml×3).The obtained resin was suspended in 1% acetic acid-dimethylformamidesolution (5 ml), and 4-phenyloxybenzaldehyde (0.252 g), and sodiumtriacetoxyborohydride (0.277 g) were added thereto. It was stirred for15 hours at room temperature. The resin was collected by filtration fromreaction mixture, and was washed with methanol (5 ml×1),dimethylformamide (5 ml×3), methanol (5 ml×4) and dichloromethane (5ml×4). The obtained resin was suspended in 50% trifluoroaceticacid-dichloromethane solution (5 ml), and it was stirred for 5 minutesat room temperature. The reaction solution was filtrated, and theobtained resin was suspended in 50% trifluoroacetic acid-dichloromethanesolution (5 ml), and it was stirred for 30 minutes at room temperature.The obtained resin by filtration from the reaction solution was washedwith dichloromethane (5 ml×3) and 1.25M acetic acid-toluene solution (5ml×3). The obtained resin was suspended in 1.25M acetic acid-toluenesolution (5 ml), and it was stirred for 23 hours at 90° C. The reactionsolution was filtrated. The obtained resin was washed withchloroform-methanol (1:1; 2 ml×2). The filtrate and the washings wereconcentrated to give the compound of the present invention (274 mg)having the following physical data.

TLC: Rf 0.40 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.49 (m, 2H),7.40 (m, 2H), 7.18 (m, 2H), 7.04 (m, 3H), 4.33 (s, 2H), 4.04 (dd, J=8.1,4.8 Hz, 1H), 3.78 (m, 2H), 3.52 (m, 2H), 3.35 (m, 2H), 2.45-2.10 (m,4H), 1.98 (s, 3H, CH3COOH), 1.97-1.58 (m, 4H), 0.94 (d, J=6.0 Hz, 6H),0.51 (m, 2H), 0.36 (m, 2H).

EXAMPLE 23(1)1-(thiophen-2-ylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenoxyphenyl)-1,3,9-triazaspiro[5.5]undecane.acetate

By the same procedure as described in Example 23 using Resin (3)prepared in Reference Example 2 (0.5 g), N-allyloxycarbonyl-4-piperidone(0.396 g), thiophen-2-ylmethylamine (0.205 ml) andN-(t-butyloxycarbonyl)leucine (0.542 g), 4-phenoxybenzaldehyde (0.252g), the compound of the present invention (274 mg) having the followingphysical data was obtained.

TLC: Rf 0.39 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.48 (m, 2H),7.39 (m, 2H), 7.28 (m, 1H), 7.18 (m, 2H), 7.04 (m, 4H), 6.91 (m, 1H),4.86 (s, 2H), 4.32 (s, 2H), 4.12 (dd, J=8.1, 4.5 Hz, 1H), 3.77 (m, 2H),3.49 (m, 2H), 2.60-2.30 (m, 2H), 2.19 (m, 2H), 1.98 (s, 3H), 1.97-1.58(m, 3H), 0.94 (d, J=6.0 Hz, 6H).

EXAMPLE 24(1) TO 24(119)

By the same procedure as described in Reference Example 3→ReferenceExample 4 using Resin (3) prepared in Reference Example 2 andN-allyloxycarbonyl-4-piperidone, using the corresponding compoundsrespectively instead of n-propylamine and N-(t-butyloxycarbonyl)leucine,and furthermore by the same procedure as described in Reference Example5→Reference Example 6→Example 1 using the corresponding compound insteadof 3,5-dimethyl-1-phenyl-4-formylpyrazole, the following compounds ofthe present invention were obtained.

EXAMPLE 24(1)(3S)-1-butyl-2,5-dioxo-3-(4-methoxyphenylmethyl)-9-cyclohexylmethyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06 (d, J=9.0Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 4.31 (dd, J=4.5, 3.6 Hz, 1H), 3.82-3.67(m, 4H), 3.49-3.30 (m, 3H), 3.25 (dd, J=13.8, 3.6 Hz, 1H), 3.23-3.10 (m,2H), 2.95-2.87 (m, 2H), 2.87 (dd, J=13.8, 4.5 Hz, 1H), 2.31 (m, 1H),2.05 (m, 1H), 1.91-1.64 (m, 7H), 1.56-1.14 (m, 7H), 1.09-0.91 (m, 5H),0.26 (m, 1H).

EXAMPLE 24(2)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-chlorophenyl)thiophen-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.65 (d, J=8.7Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.42 (d, J=3.6 Hz, 1H), 7.34 (d, J=3.6Hz, 1H), 4.61 (brs, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.95-3.72 (m,2H), 3.65-3.50 (m, 2H), 3.44-3.34 (m, 2H), 2.50-2.12 (m, 4H), 1.89-1.45(m, 5H), 1.45-1.28 (m, 2H), 1.13-0.89 (m, 9H).

EXAMPLE 24(3)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-methoxyphenyl)thiophen-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.57 (d, J=9.0Hz, 2H), 7.33-7.26 (m, 2H), 6.97 (d, J=9.0 Hz, 2H), 4.58 (brs, 2H), 4.01(dd, J=7.5, 4.5 Hz, 1H), 3.93-3.71 (m, 5H), 3.64-3.50 (m, 2H), 3.44-3.34(m, 2H), 2.49-2.12 (m, 4H), 1.90-1.45 (m, 5H), 1.45-1.28 (m, 2H),1.03-0.88 (m, 9H).

EXAMPLE 24(4)1-((2E)-2-butenyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.32 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.52 (d, J=8.7Hz, 2H), 7.44-7.35 (m, 2H), 7.22-7.14 (m, 1H), 7.06 (d, J=8.7 Hz, 2H),7.10-7.00 (m, 2H), 5.75-5.60 (m, 1H), 5.52-5.38 (m, 1H), 4.33 (s, 2H),4.15-3.93 (m, 2H), 4.03 (dd, J=7.8, 4.5 Hz, 1H), 3.88-3.66 (m, 2H),3.55-3.42 (m, 2H), 2.52-2.35 (m, 2H), 2.28-2.08 (m, 2H), 1.90-1.57 (m,3H), 1.65 (dd, J=6.3, 1.5 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.94 (d,J=6.6 Hz, 3H).

EXAMPLE 24(5)1-(furan-2-ylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.52 (d, J=8.7Hz, 2H), 7.43-7.36 (m, 3H), 7.18 (t, J=7.2 Hz, 1H), 7.09-6.99 (m, 4H),6.33 (m, 1H), 6.28 (d, J=3.0 Hz, 1H), 4.69 (s, 2H), 4.33 (s, 2H), 4.08(dd, J=7.8, 4.5 Hz, 1H), 3.87-3.72 (m, 2H), 3.57-3.42 (m, 2H), 2.65-2.38(m, 2H), 2.30-2.12 (m, 2H), 1.90-1.56 (m, 3H), 0.93 (d, J=6.6 Hz, 3H),0.91 (d, J=6.6 Hz, 3H).

EXAMPLE 24(6)1-(thiophen-2-ylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.39 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.43-7.34 (m, 2H), 7.27 (dd, J=5.1, 1.2 Hz, 1H), 7.18 (t, J=7.2Hz, 1H), 7.09-7.00 (m, 5H), 6.91 (dd, J=5.1, 3.3 Hz, 1H), 4.92 (brs,2H), 4.32 (s, 2H), 4.11 (dd, J=7.8, 4.5 Hz, 1H), 3.84-3.66 (m, 2H),3.53-3.41 (m, 2H), 2.68-2.46 (m, 2H), 2.23-2.06 (m, 2H), 1.95-1.59 (m,3H), 0.95 (d, J=6.6 Hz, 6H).

EXAMPLE 24(7)1-cyclopropylmethyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.40 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.43-7.35 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.08-7.00 (m, 4H),4.33 (s, 2H), 4.04 (dd, J=7.8, 4.5 Hz, 1H), 3.87-3.68 (m, 2H), 3.56-3.43(m, 2H), 3.46-3.35 (m 2H), 2.56-2.35 (m, 2H), 2.23-2.12 (m, 2H),1.95-1.58 (m, 3H), 1.10-0.95 (m, 1H), 0.95 (d, J=6.6 Hz, 6H), 0.56-0.45(m, 2H), 0.42-0.34 (m, 2H).

EXAMPLE 24(8)1-(2-fluorophenylmethyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.48 (d, J=9.0Hz, 2H), 7.42-7.34 (m, 2H), 7.32-7.21 (m, 1H), 7.17 (t, J=7.5 Hz, 1H),7.14-7.06 (m, 3H), 7.06-6.98 (m, 4H), 4.80 (brs, 2H), 4.30 (s, 2H), 4.18(dd, J=8.1, 4.8 Hz, 1H), 3.86-3.68 (m, 2H), 3.50-3.35 (m, 2H), 2.50-2.30(m, 1H), 2.30-2.14 (m, 3H), 1.94-1.62 (m, 3H), 0.97 (d, J=6.3 Hz, 6H).

EXAMPLE 24(9)1-(3-methyl-2-butenyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.29 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.52 (d, J=8.4Hz, 2H), 7.43-7.35 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.09-7.00 (m, 4H),4.97 (br, 1H), 4.32 (s, 2H), 4.20-4.00 (m, 2H), 4.02 (dd, J=7.8, 4.5 Hz,1H), 3.90-3.68 (m, 2H), 3.55-3.45 (m, 2H), 2.52-2.32 (m, 2H), 2.30-2.08(m, 2H), 1.90-1.56 (m, 3H), 1.74 (s, 3H), 1.69 (s, 3H), 0.94 (d, J=6.3Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 24(10)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(quinolin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.25 (chloroform:methanol=20:1); NMR (CD₃OD): δ 9.52 (d, J=1.5Hz, 1H), 9.35 (d, J=1.5 Hz, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.27 (d, J=8.7Hz, 1H), 8.24-8.16 (m, 1H), 8.04-7.96 (m, 1H), 4.76 (s, 2H), 4.03 (dd,J=7.5, 4.5 Hz, 1H), 4.00-3.85 (m, 2H), 3.68-3.55 (m, 2H), 3.55-3.43 (m,2H), 2.76-2.56 (m, 2H), 2.27-2.05 (m, 2H), 1.82-1.10 (m, 15H), 1.05-0.83(m, 2H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 24(11)1-butyl-2,5-dioxo-3-(benzyloxycarbonylmethyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.74 (chloroform:methanol=9:1); NMR (CD₃OD): δ 7.52 (d, J=7.0Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.33 (m, 5H), 7.18 (t, J=7.5 Hz, 1H),7.05 (m, 4H), 5.12 (s, 2H), 4.33 (s, 2H), 4.31 (m, 1H), 3.88 (m, 1H),3.66 (m, 1H), 3.50-3.35 (m, 4H), 3.08 (dd, J=17.7, 4.8 Hz, 1H), 2.86(dd, J=17.7, 3.0 Hz, 1H), 2.34 (m, 2H), 2.25 (m, 2H), 1.50 (m, 2H), 1.36(m, 2H), 0.94 (t, J=7.5 Hz, 3H).

EXAMPLE 24(12)1-(3-methyl-2-butenyl)-2,5-dioxo-3-cyclohexylmethyl-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.1Hz, 1H), 6.96 (dd, J=8.1, 2.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.96 (m,1H), 4.26 (s, 4H), 4.22 (s, 2H), 4.10-4.00 (m, 3H), 3.84-3.68 (m, 2H),3.52-3.40 (m, 2H), 2.43-2.08 (m, 4H), 1.84-1.42 (m, 13H), 1.38-1.12 (m,4H), 1.04-0.85 (m, 2H).

EXAMPLE 24(13)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-((2E)-3-phenyl-2-propenyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.53-7.48 (m,2H), 7.30-7.40 (m, 3H), 6.95 (d, J=16.2 Hz, 1H), 6.36 (dd, J=16.2, 8.1Hz, 1H), 4.07 (dd, J=7.5, 4.5 Hz, 1H), 3.96 (d, J=8.1 Hz, 2H), 3.86-3.75(m, 2H), 3.60-3.52 (m, 2H), 3.42-3.34 (m, 2H), 2.42-2.18 (m, 4H),1.82-1.14 (m, 15H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 24(14)(3S)-1-butyl-2,5-dioxo-3-(1,1-dimethylethyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54 (d, J=8.5Hz, 2H), 7.39 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.08-7.02 (m, 4H), 4.34(s, 2H), 3.88 (m, 2H), 3.62 (s, 1H), 3.46 (m, 4H), 2.45 (m, 2H), 2.13(m, 2H), 1.66-1.47 (m, 2H), 1.36 (m, 2H), 1.02 (s, 9H), 0.95 (t, J=7.0Hz, 3H).

EXAMPLE 24(15)(3S)-1-butyl-2,5-dioxo-3-(1,1-dimethylethyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.07 (m, 1H),6.99 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.26 (m, 4H), 4.24 (s,2H), 3.83 (m, 2H), 3.62 (s, 1H), 3.45 (m, 4H), 2.42 (m, 2H), 2.11 (m,2H), 1.64-1.5 (m, 2H), 1.38 (m, 2H), 1.01 (s, 9H), 0.95 (t, J=7.0 Hz,3H).

EXAMPLE 24(16)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylthiazol-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.67 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.34 (s, 1H),4.73 (s, 2H), 4.01 (dd, J=8.0, 4.5 Hz, 1H), 3.93 (m, 2H), 3.65 (m, 2H),3.41 (m, 2H), 2.53-2.41 (m, 2H), 2.48 (s, 3H), 2.23 (m, 2H), 1.85-1.52(m, 5H), 1.38 (m, 2H), 0.96 (t, J=7.0 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H),0.93 (d, J=6.5 Hz, 3H).

EXAMPLE 24(17)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(5-methylthiazol-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.66 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.34 (s, 1H),4.72 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.98-3.86 (m, 2H), 3.67-3.63(m, 2H), 3.44-3.38 (m, 2H), 2.56-2.42 (m, 2H), 2.48 (s, 3H), 2.30-2.14(m, 2H), 1.84-1.18 (m, 15H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 24(18)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylthiazol-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.63 (s, 1H),4.69 (s, 2H), 4.03 (dd, J=7.3, 4.5 Hz, 1H), 3.96-3.82 (m, 2H), 3.72-3,58(m, 2H), 3.42-3.37 (m, 2H), 2.52 (s, 3H), 2.56-2.36 (m, 2H), 2.28-2.12(m, 2H), 1.80-1.12 (m, 15H), 0.96 (t, J=7.5 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 24(19)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(5-methylthiazol-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.70 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.63 (s, 1H),4.69 (brs, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.99-3.83 (m, 2H),3.70-3.58 (m, 2H), 3.44-3.34 (m, 2H), 2.53 (s, 3H), 2.50-2.33 (m, 2H),2.32-2.12 (m, 2H), 1.88-1.46 (m, 5H), 1.45-1.31 (m, 2H), 1.01-0.90 (m,9H).

EXAMPLE 24(20)(3R)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.0Hz, 1H), 6.97 (dd, J=8.5, 2.0 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.26 (s,4H), 4.24 (s, 2H), 4.04 (dd, J=7.5, 5.0 Hz, 1H), 3.76 (m, 2H), 3.46 (m,4H), 2.39-2.11 (m, 4H), 1.78-1.17 (m, 15H), 0.95 (t, J=7.0 Hz, 3H), 0.95(m, 2H). HPLC condition Column: YMC CHIRAL-CD BR, 0.46×25 cm, YMC,DB12S05-2546WTI; Flow rate: 0.5 mL/min; eluent Component A: 0.1Mpotassium dihydrogenphosphate aqueous solution Component B: acetonitrileA:B=84:16; UV: 235 nm; Retention time: 18 min.

EXAMPLE 24(21)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.0Hz, 1H), 6.97 (dd, J=8.5, 2.0 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.26 (s,4H), 4.24 (s, 2H), 4.04 (dd, J=7.5, 5.0 Hz, 1H), 3.76 (m, 2H), 3.46 (m,4H), 2.39-2.11 (m, 4H), 1.78-1.17 (m, 15H), 0.95 (t, J=7.0 Hz, 3H), 0.95(m, 2H). HPLC condition Column: YMC CHIRAL-CD BR, 0.46×25 cm, YMC,DB12S05-2546WTI; Flow rate: 0.5 mL/min; Eluent Component A: 0.1Mpotassium dihydrogenphosphate aqueous solution Component B: acetonitrileA:B=84:16; UV: 235 nm; Retention time: 20 min.

EXAMPLE 24(22)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.5Hz, 2H), 7.39 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.08-7.01 (m, 4H), 4.33(s, 2H), 3.96 (d, J=2.5 Hz, 1H), 3.92 (m, 1H), 3.75 (m, 1H), 3.53-3.44(m, 4H), 2.49-2.32 (m, 2H), 2.16 (m, 2H), 2.06-1.98 (m, 1H), 1.61-1.21(m, 6H), 1.00-0.89 (m, 9H).

EXAMPLE 24(23)(3S)-1-butyl-2,5-dioxo-3-((1S)-1-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.5Hz, 2H), 7.39 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.08-7.01 (m, 4H), 4.33(s, 2H), 3.96 (d, J=2.5 Hz, 1H), 3.92 (m, 1H), 3.75 (m, 1H), 3.53-3.44(m, 4H), 2.49-2.32 (m, 2H), 2.16 (m, 2H), 2.06-1.98 (m, 1H), 1.61-1.21(m, 6H), 1.00-0.89 (m, 9H).

EXAMPLE 24(24)1-(2-butynyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.70 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.2 Hz, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.09-7.00(m, 4H), 4.33 (brs, 2H), 4.28-4.10 (m, 2H), 4.05 (dd, J=7.8, 4.5 Hz,1H), 3.86-3.70 (m, 2H), 3.56-3.43 (m, 2H), 2.59-2.40 (m, 2H), 2.34-2.15(m, 2H), 1.89-1.57 (m, 6H), 0.94 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz,3H).

EXAMPLE 24(25)1-(2-butynyl)-2,5-dioxo-3-cyclohexylmethyl-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.1Hz, 1H), 6.97 (dd, J=8.4, 2.1 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.26 (s,4H), 4.23 (s, 2H), 4.18 (brs, 2H), 4.07 (dd, J=6.9, 4.8 Hz, 1H),3.84-3.68 (m, 2H), 3.55-3.42 (m, 2H), 2.57-2.40 (m, 2H), 2.32-2.12 (m,2H), 1.85-1.42 (m, 11H), 1.38-1.13 (m, 3H), 1.04-0.85 (m, 2H).

EXAMPLE 24(26)1-pentyl-2,5-dioxo-3-cyclohexylmethyl-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.1Hz, 1H), 6.97 (dd, J=8.4, 2.1 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.26 (s,4H), 4.22 (brs, 2H), 4.03 (dd, J=7.2, 4.5 Hz, 1H), 3.84-3.67 (m, 2H),3.52-3.33 (m, 4H), 2.43-2.07 (m, 4H), 1.83-1.42 (m, 9H), 1.41-1.13 (m,8H), 1.04-0.85 (m, 5H).

EXAMPLE 24(27)1-(3-methoxyphenylmethyl)-2,5-dioxo-3-(benzyloxymethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.60-7.43 (m,5H), 7.38-7.24 (m, 5H), 7.14 (t, J=8.4 Hz, 1H), 6.83-6.72 (m, 3H),4.96-4.70 (m, 2H), 4.60 (d, J=11.4 Hz, 1H), 4.50 (d, J=11.4 Hz, 1H),4.29 (t, J=2.4 Hz, 1H), 4.24 (s, 2H), 4.02 (dd, J=9.6, 2.4 Hz, 1H),3.93-3.79 (m, 1H), 3.72 (s, 3H), 3.70 (dd, J=9.6, 2.4 Hz, 1H), 3.70-3.60(m, 1H), 3.55-3.44 (m, 1H), 3.35-3.23 (m, 1H), 2.58-2.05 (m, 10H).

EXAMPLE 24(28)(3R)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.29 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54 (d, J=8.7Hz, 2H), 7.42-7.36 (m, 2H), 7.18 (m, 1H), 7.05 (d, J=8.7 Hz, 2H),7.05-7.02 (m, 2H), 4.32 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.85-3.72(m, 2H), 3.50-3.39 (m, 4H), 2.52-2.38 (m, 2H), 2.24-2.11 (m, 2H),1.84-1.20 (m, 7H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.93(d, J=6.3 Hz, 3H). HPLC condition Column: CHIRALCEL OD-R, 0.46×25 cm,DAICEL, ODR0CE-HD028; Flow rate: 0.4 mL/min; Eluent Component A: 0.2Mpotassium dihydrogenphosphate aqueous solution Component B: acetonitrileA:B=64:36; UV: 235 nm; Retention time: 30 min.

EXAMPLE 24(29)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.29 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54 (d, J=8.7Hz, 2H), 7.42-7.36 (m, 2H), 7.18 (m, 1H), 7.05 (d, J=8.7 Hz, 2H),7.05-7.02 (m, 2H), 4.33 (s, 2H), 3.98 (dd, J=8.1, 4.5 Hz, 1H), 3.86-3.72(m, 2H), 3.53-3.37 (m, 4H), 2.47-2.36 (m, 2H), 2.24-2.12 (m, 2H),1.80-1.30 (m, 7H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.93(d, J=6.3 Hz, 3H). HPLC condition Column: CHIRALCEL OD-R, 0.46×25 cm,DAICEL, ODR0CE-HD028; Flow rate: 0.4 mL/min; Eluent Component A: 0.2Mpotassium dihydrogenphosphate aqueous solution Component B: acetonitrileA:B=64:36; UV: 235 nm; Retention time: 28 min.

EXAMPLE 24(30)1-butyl-2,5-dioxo-3-cyclopentylmethyl-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.05 (d, J=2.0Hz, 1H), 6.98 (dd, J=8.5, 2.0 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.26 (s,4H), 4.23 (s, 2H), 3.99 (t, J=6.0 Hz, 1H), 3.77 (m, 2H), 3.46 (m, 2H),3.37 (m, 2H), 2.36 (m, 2H), 2.15 (m, 2H), 1.96 (m, 1H), 1.81 (m, 4H),1.59 (m, 6H), 1.36 (m, 2H), 1.15 (m, 2H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 24(31)1-propyl-2,5-dioxo-3-(cyclohexylmethyloxymethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.59-7.46 (m,5H), 4.33 (s, 2H), 4.08 (m, 1H), 4.00 (m, 1H), 3.83 (m, 1H), 3.77 (m,1H), 3.59 (m, 2H), 3.52 (m, 1H), 3.25 (d, J=6.5 Hz, 2H), 2.53 (m, 2H),2.42 (m, 1H), 2.40 (s, 3H), 2.39 (s, 3H), 2.21 (m, 2H), 1.69 (m, 6H),1.52 (m, 2H), 1.21 (m, 4H), 0.95 (t, J=7.0 Hz, 3H), 0.88 (m, 2H).

EXAMPLE 24(32)(3S)-1-butyl-2,5-dioxo-3-(1-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06-6.90 (m,3H), 4.26 (s, 4H), 4.23 (s, 2H), 3.95 (d, J=3.3 Hz, 1H), 3.87 (m, 1H),3.70 (m, 1H), 3.58-3.42 (m, 4H), 2.56-2.30 (m, 2H), 2.20-1.98 (m, 2H),1.54-1.00 (m, 7H), 0.99 (d, J=7.2 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H), 0.91(t, J=7.5 Hz, 3H).

EXAMPLE 24(33)(3R)-1-butyl-2,5-dioxo-3-(1-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06-6.91 (m,3H), 4.26 (s, 4H), 4.23 (s, 2H), 3.95 (d, J=3.3 Hz, 1H), 3.87 (m, 1H),3.70 (m, 1H), 3.56-3.40 (m, 4H), 2.50-2.32 (m, 2H), 2.18-1.96 (m, 2H),1.62-1.17 (m, 7H), 0.99 (d, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.91(t, J=7.5 Hz, 3H).

EXAMPLE 24(34)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(5-phenylmethylthiophen-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.56 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.32-7.21 (m,5H), 7.17 (d, J=3.6 Hz, 1H), 6.89 (d, J=3.6 Hz, 1H), 4.51 (s, 2H), 4.17(s, 2H), 4.00 (dd, J=7.8 Hz, 4.5 Hz, 1H), 3.84-3.72 (m, 2H), 3.56-3.44(m, 2H), 3.38-3.32 (m, 2H), 2.42-2.14 (m, 4H), 1.84-1.30 (m, 7H), 0.95(t, J=6.9 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H).

EXAMPLE 24(35)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-phenylmethylthiophen-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.32-7.21 (m,5H), 7.18 (d, J=3.6 Hz, 1H), 6.89 (d, J=3.6 Hz, 1H), 4.51 (s, 2H), 4.17(s, 2H), 4.03 (dd, J=7.8, 4.8 Hz, 1H), 3.84-3.72 (m, 2H), 3.58-3.44 (m,2H), 3.40-3.36 (m, 2H), 2.44-2.08 (m, 4H), 1.81-1.07 (m, 15H), 0.95 (t,J=7.2 Hz, 3H), 0.95 (m, 2H).

EXAMPLE 24(36)(3R)-1-butyl-2,5-dioxo-3-(2,2-dimethylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.05 (s, 1H),6.98 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.26 (s, 4H), 4.23 (s,2H), 4.00 (dd, J=7.0, 3.0 Hz, 1H), 3.83-3.64 (m, 2H), 3.50 (m, 2H), 3.38(m, 2H), 2.35 (m, 2H), 2.25 (m, 2H), 1.99 (m, 1H), 1.55 (m, 1H), 1.50(m, 2H), 1.35 (m, 2H), 0.99 (s, 9H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 24(37)(3S)-1-butyl-2,5-dioxo-3-(2,2-dimethylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.05 (s, 1H),6.98 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.26 (s, 4H), 4.23 (s,2H), 4.00 (dd, J=7.0, 3.0 Hz, 1H), 3.83-3.63 (m, 2H), 3.50 (m, 2H), 3.38(m, 2H), 2.35 (m, 2H), 2.25 (m, 2H), 1.99 (dd, J=14.0, 3.0 Hz, 1H), 1.55(dd, J=14.0, 7.0 Hz, 1H), 1.50 (m, 2H), 1.35 (m, 2H), 0.99 (s, 9H), 0.95(t, J=7.0 Hz, 3H).

EXAMPLE 24(38)(3R)-1-(2-butynyl)-2,5-dioxo-3-(2,2-dimethylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10-7.00(m, 4H), 4.33 (brs, 2H), 4.33-4.09 (m, 2H), 4.03 (dd, J=6.9, 3.3 Hz,1H), 3.85-3.68 (m, 2H), 3.58-3.43 (m, 2H), 2.59-2.41 (m, 2H), 2.40-2.20(m, 2H), 2.03 (dd, J=14.4, 3.3 Hz, 1H), 1.75 (brs, 3H), 1.56 (dd,J=14.4, 6.9 Hz, 1H), 0.99 (s, 9H).

EXAMPLE 24(39)(3S)-1-(2-butynyl)-2,5-dioxo-3-(2,2-dimethylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10-7.00(m, 4H), 4.33 (brs, 2H), 4.33-4.09 (m, 2H), 4.03 (dd, J=6.9, 3.3 Hz,1H), 3.85-3.68 (m, 2H), 3.58-3.43 (m, 2H), 2.59-2.41 (m, 2H), 2.40-2.20(m, 2H), 2.03 (dd, J=14.4, 3.3 Hz, 1H), 1.75 (brs, 3H), 1.56 (dd,J=14.4, 6.9 Hz, 1H), 0.99 (s, 9H).

EXAMPLE 24(40)1-butyl-2,5-dioxo-3-cycloheptylmethyl-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.70 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.1Hz, 1H), 6.97 (dd, J=8.4, 2.1 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.26 (s,4H), 4.24 (s, 2H), 3.99 (dd, J=8.1, 4.2 Hz, 1H), 3.84-3.70 (m, 2H), 3.45(m, 2H), 3.36 (m, 2H), 2.37-2.11(m, 4H), 1.80-1.49 (m, 15H), 1.36 (m,2H), 1.22 (m, 2H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 24(41)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2,4,6-trimethoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CD₃OD): δ 6.31 (s, 2H),4.26 (s, 2H), 4.03 (dd, J=7.8, 4.5 Hz, 1H), 3.89 (s, 6H), 3.84 (s, 3H),3.84-3.73 (m, 2H), 3.54-3.33 (m, 4H), 2.44-2.25 (m, 2H), 2.24-2.03 (m,2H), 1.84-1.12 (m, 15H), 1.06-0.85 (m, 5H).

EXAMPLE 24(42)1-butyl-2,5-dioxo-3-(3-cyclohexylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.71 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.05-6.91 (m,3H), 4.26 (s, 4H), 4.22 (s, 2H), 4.04 (t, J=5.4 Hz, 1H), 3.84 (m, 1H),3.67 (m, 1H), 3.54-3.40 (m, 3H), 3.35 (m, 1H), 2.44-2.08 (m, 4H),1.90-1.16 (m, 19H), 0.95 (t, J=7.5 Hz, 3H), 0.95 (m, 2H).

EXAMPLE 24(43)1-butyl-2,5-dioxo-3-(3-cyclohexylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.76 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53-7.49 (m,2H), 7.42-7.36 (m, 2H), 7.18 (m, 1H), 7.10-7.02 (m, 4H), 4.32 (s, 2H),4.04 (t, J=4.8 Hz, 1H), 3.87 (m, 1H), 3.71 (m, 1H), 3.56-3.40 (m, 3H),3.35 (m, 1H), 2.48-2.12 (m, 4H), 1.86-1.10 (m, 19H), 0.95 (t, J=7.5 Hz,3H), 0.95 (m, 2H).

EXAMPLE 24(44)1-butyl-2,5-dioxo-3-(3-cyclohexylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.64 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.59-7.45 (m,5H), 4.31 (s, 2H), 4.06 (t, J=5.0 Hz, 1H), 3.92 (m, 1H), 3.77 (m, 1H),3.63-3.37 (m, 4H), 2.44 (m, 2H), 2.39 (s, 3H), 2.38 (s, 3H), 2.21 (m,2H), 1.85-1.68 (m, 7H), 1.54 (m, 2H), 1.39 (m, 4H), 1.23 (m, 6H), 0.96(t, J=7.5 Hz, 3H), 0.89 (m, 2H).

EXAMPLE 24(45)1-butyl-2,5-dioxo-3-(2-hydroxy-2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.09-7.00(m, 4H), 4.32 (brs, 2H), 4.29 (dd, J=9.9, 3.0 Hz, 1H), 4.04-3.88 (m,2H), 3.59-3.40 (m, 4H), 2.46-2.21 (m, 4H), 2.18 (dd, J=14.4, 3.0 Hz,1H), 1.75 (dd, J=14.4, 9.9 Hz, 1H), 1.61-1.43 (m, 2H), 1.42-1.29 (m,2H), 1.28 (s, 6H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 24(46)1-(2-butynyl)-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.45 (m,5H), 4.32 (s, 2H), 4.31-4.18 (m, 2H), 4.06 (dd, J=7.8, 4.5 Hz, 1H),3.93-3.77 (m, 2H), 3.68-3.57 (m, 2H), 2.72-2.57 (m, 2H), 2.40 (s, 3H),2.38 (s, 3H), 2.36-2.16 (m, 2H), 1.92-1.59 (m, 6H), 0.95 (d, J=6.6 Hz,3H), 0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 24(47)1-(2-butynyl)-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.37 (chloroform:methanol=10:1); NMR (CD₃OD): 7.60-7.43 (m, 5H),4.32 (s, 2H), 4.23 (d, J=2.1 Hz, 2H), 4.09 (dd, J=7.2, 4.8 Hz, 1H),3.92-3.78 (m, 2H), 3.68-3.56 (m, 2H), 2.66-2.51 (m, 2H), 2.38 (s, 3H),2.36 (s, 3H), 2.36-2.16 (m, 2H), 1.83-1.60 (m, 10H), 1.59-1.43 (m, 1H),1.38-1.12 (m, 3H), 1.06-0.87 (m, 2H).

EXAMPLE 24(48)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.35 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.63-7.48 (m,5H), 4.33 (s, 2H), 4.05 (dd, J=7.8, 4.5 Hz, 1H), 3.95-3.74 (m, 2H),3.67-3.56 (m, 2H), 3.48 (m, 2H), 2.72-2.58 (m, 2H), 2.45 (s, 3H), 2.41(s, 3H), 2.30-2.07 (m, 2H), 1.84-1.10 (m, 15H), 1.02-0.92 (m, 2H), 0.96(t, J=7.2 Hz, 3H).

EXAMPLE 24(49)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-phenyloxypyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.23 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.19 (m, 1H),8.07 (m, 1H), 7.47-7.42 (m, 2H), 7.29-7.19 (m, 4H), 4.55 (s, 2H), 4.03(dd, J=7.8, 4.5 Hz, 1H), 3.94 (m, 2H), 3.64 (m, 2H), 3.38 (m, 2H),2.54-2.16 (m, 4H), 1.90-1.28 (m, 7H), 0.96 (t, J=6.9 Hz, 3H), 0.96 (d,J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 24(50)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-phenyloxypyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.62 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.19 (m, 1H),8.09 (m, 1H), 7.47-7.42 (m, 2H), 7.29-7.19 (m, 4H), 4.55 (s, 2H), 4.05(dd, J=7.8, 4.8 Hz, 1H), 3.96 (m, 2H), 3.64 (m, 2H), 3.42 (m, 2H), 2.48(m, 2H), 2.36-2.16 (m, 2H), 1.82-1.14 (m, 15H), 0.96 (t, J=7.5 Hz, 3H),0.95-0.84 (m, 2H).

EXAMPLE 24(51)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylbenzomorpholin-7-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.69 (chloroform:methanol=10:1); NMR (CDCl₃): δ 6.93 (d, J=8.7Hz, 1H), 6.86 (s, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.28-4.25 (m, 2H), 4.17(s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.80-3.65 (m, 2H), 3.50-3.40 (m,2H), 3.40-3.30 (m, 2H), 2.91 (s, 3H), 2.38-2.06 (m, 4H), 1.78-1.63 (m,8H), 1.63-1.42 (m, 3H), 1.40-1.18 (m, 6H), 1.05-0.90 (m, 2H), 0.95 (t,J=7.2 Hz, 3H).

EXAMPLE 24(52)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylbenzomorpholin-7-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.56 (chloroform:methanol=10:1); NMR (CDCl₃): δ 7.00 (d, J=7.2Hz, 1H), 6.94 (s, 1H), 6.85 (d, J=7.2 Hz, 1H), 4.31-4.29 (m, 2H), 4.19(s, 2H), 4.00 (dd, J=7.8, 4.5 Hz, 1H), 3.79-3.66 (m, 2H), 3.47-3.34 (m,6H), 2.97 (s, 3H), 2.45-2.34 (m, 2H), 2.22-2.10 (m, 2H), 1.84-1.75 (m,1H), 1.71-1.46 (m, 4H), 1.42-1.32 (m, 2H), 0.97-0.92 (m, 9H).

EXAMPLE 24(53)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N-methyl-N-phenylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.40 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.40-7.28 (m,4H), 7.19-7.10 (m, 3H), 6.94-6.86 (m, 2H), 4.23 (s, 2H), 4.00 (dd,J=7.8, 4.5 Hz, 1H), 3.86-3.63 (m, 2H), 3.55-3.30 (m, 4H), 3.31 (s, 3H),2.46-2.27 (m, 2H), 2.26-2.06 (m, 2H), 1.90-1.42 (m, 5H), 1.44-1.26 (m,2H), 0.98-0.91 (m, 9H).

EXAMPLE 24(54)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N-methyl-N-phenylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.52 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.40-7.28 (m,4H), 7.20-7.12 (m, 3H), 6.93-6.86 (m, 2H), 4.24 (s, 2H), 4.03 (dd,J=7.5, 4.8 Hz, 1H), 3.85-3.66 (m, 2H), 3.55-3.40 (m, 2H), 3.40-3.30 (m,2H), 3.32 (s, 3H), 2.44-2.07 (m, 4H), 1.84-1.40 (m, 10H), 1.40-1.10 (m,5H), 1.06-0.85 (m, 2H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 24(55)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(3,5-dimethylpyrazol-1-yl)-5-methoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.58 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=3.0Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.22 (dd, J=8.7, 3.0 Hz, 1H), 6.29 (s,1H), 4.09 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.94 (s, 3H), 3.74 (m,2H), 3.42 (m, 4H), 2.44 (m, 2H), 2.37 (s, 3H), 2.22 (s, 3H), 2.22 (m,2H), 1.86-1.30 (m, 7H), 0.96 (t, J=7.8 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H),0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 24(56)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-(3,5-dimethylpyrazol-1-yl)-5-methoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.43 (d, J=8.7Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.22 (s,1H), 4.09 (s, 2H), 4.06 (dd, J=7.5, 4.2 Hz, 1H), 3.93 (s, 3H), 3.80 (m,2H), 3.42 (m, 4H), 2.38 (m, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 2.20 (m,2H), 1.80-1.16 (m, 15H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 24(57)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-diethyl-1-(4-chlorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.47 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.53 (d, J=9.0Hz, 2H), 7.49 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz,1H), 3.94-3.73 (m, 2H), 3.65-3.54 (m, 2H), 3.49-3.38 (m, 2H), 2.88 (q,J=7.5 Hz, 2H), 2.77 (q, J=7.5 Hz, 2H), 2.58-2.38 (m, 2H), 2.30-2.12 (m,2H), 1.90-1.56 (m, 5H), 1.55-1.30 (m, 2H), 1.31 (t, J=7.5 Hz, 3H),0.99-0.94 (m, 12H).

EXAMPLE 24(58)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-diethyl-1-(4-chlorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.51 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.58 (d, J=9.0Hz, 2H), 7.48 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz,1H), 3.94-3.73 (m, 2H), 3.65-3.54 (m, 2H), 3.50-3.38 (m, 2H), 2.88 (q,J=7.5 Hz, 2H), 2.77 (q, J=7.5 Hz, 2H), 2.60-2.40 (m, 2H), 2.28-2.09 (m,2H), 1.85-1.10 (m, 15H), 1.31 (t, J=7.5 Hz, 3H), 1.04-0.85 (m, 2H), 0.96(t, J=7.5 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H).

EXAMPLE 24(59)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(6-phenyloxypyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.65 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.32 (s, 1H),8.06 (m, 1H), 7.44 (t, J=7.5 Hz, 2H), 7.26 (t, J=7.5 Hz, 1H), 7.14 (d,J=7.5 Hz, 2H), 7.06 (d, J=8.7 Hz, 1H), 4.39 (s, 2H), 4.01 (dd, J=7.5,4.5 Hz, 1H), 3.90-3.70 (m, 2H), 3.53-3.41 (m, 4H), 2.45 (m, 2H),2.25-2.12 (m, 2H), 1.78 (m, 1H), 1.72-1.50 (m, 4H), 1.36 (m, 2H),0.97-0.93 (m, 9H).

EXAMPLE 24(60)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(6-phenyloxypyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.67 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.31 (s, 1H),8.07 (d, J=8.3 Hz, 1H), 7.44 (t, J=7.5 Hz, 2H), 7.26 (t, J=7.5 Hz, 1H),7.14 (d, J=7.5 Hz, 2H), 7.06 (d, J=8.3 Hz, 1H), 4.39 (s, 2H), 4.04 (dd,J=7.8, 4.6 Hz, 1H), 3.90-3.76 (m, 2H), 3.52-3.38 (m, 4H), 2.58-2.36 (m,2H), 2.25-2.11 (m, 2H), 1.80-1.42 (m, 10H), 1.42-1.17 (m, 5H), 1.05-0.85(m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 24(61)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(1,3-benzodioxolan-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.05-7.00 (m,2H), 6.92 (m, 1H), 6.03 (s, 2H), 4.26 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz,1H), 3.84-3.68 (m, 2H), 3.52-3.36 (m, 4H), 2.42-2.10 (m, 4H), 1.88-1.32(m, 7H), 0.96 (t, J=6.9 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3Hz, 3H).

EXAMPLE 24(62)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(1,3-benzodioxolan-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06-7.01 (m,2H), 6.92 (m, 1H), 6.03 (s, 2H), 4.27 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz,1H), 3.82-3.70 (m, 2H), 3.56-3.36 (m, 4H), 2.48-2.10 (m, 4H), 1.82-1.16(m, 15H), 0.96 (t, J=7.5 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 24(63)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-hydroxy-4-methoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.88 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.26 (d, J=8.5Hz, 1H), 6.51 (dd, J=8.5, 2.5 Hz, 1H), 6.48 (d, J=2.5 Hz, 1H), 4.26 (s,2H), 4.03 (m, 1H), 3.77 (m, 5H), 3.47 (m, 2H), 3.37 (m, 2H), 2.34 (m,2H), 2.15 (m, 2H), 1.69 (m, 6H), 1.52 (m, 4H), 1.31 (m, 5H), 0.95 (m,5H).

EXAMPLE 24(64)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylthiophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.83 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.44 (d, J=8.7Hz, 2H), 7.36 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.80 (m, 2H), 3.49 (m, 2H), 3.34 (m, 2H), 2.50 (s, 3H), 2.36-2.11(m, 4H), 1.69 (m, 10H), 1.39-1.23 (m, 5H), 0.95 (m, 5H).

EXAMPLE 24(65)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N,N-diphenylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.40-7.25 (m,6H), 7.13-7.01 (m, 8H), 4.27 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H),3.87-3.68 (m, 2H), 3.56-3.44 (m, 2H), 3.44-3.32 (m, 2H), 2.48-2.32 (m,2H), 2.29-2.10 (m, 2H), 1.90-1.44 (m, 5H), 1.44-1.30 (m, 2H), 0.96 (t,J=6.9 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 24(66)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N,N-diphenylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.53 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.41-7.26 (m,6H), 7.14-7.00 (m, 8H), 4.27 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H),3.88-3.68 (m, 2H), 3.57-3.45 (m, 2H), 3.44-3.36 (m, 2H), 2.48-2.32 (m,2H), 2.28-2.07 (m, 2H), 1.84-1.44 (m, 10H), 1.44-1.14 (m, 5H), 1.00-0.90(m, 2H), 0.96 (t, J=6.9 Hz, 3H).

EXAMPLE 24(67)(3S)-1-(2-butynyl)-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.32 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.59-7.46 (m,5H), 4.32 (s, 2H), 4.24 (s, 2H), 4.09 (dd, J=7.5, 4.5 Hz, 1H), 3.86 (m,2H), 3.65 (m, 2H), 2.60 (m, 2H), 2.39 (s, 3H), 2.38 (s, 3H), 2.26 (m,2H), 1.88-1.66 (m, 10H), 1.53 (m, 1H), 1.25 (m, 3H), 0.96 (m, 2H).

EXAMPLE 24(68)(3S)-1-(2-butynyl)-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.43 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.60-7.46 (m,5H), 4.32 (s, 2H), 4.26 (m, 2H), 4.06 (dd, J=7.5, 4.5 Hz, 1H), 3.85 (m,2H), 3.62 (m, 2H), 2.60 (m, 2H), 2.39 (s, 3H), 2.38 (s, 3H), 2.27 (m,2H), 1.89-1.61 (m, 6H), 0.95 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H).

EXAMPLE 24(69)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.57 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.59-7.45 (m,5H), 4.32 (s, 2H), 4.06 (dd, J=7.8, 4.5 Hz, 1H), 3.85 (m, 2H), 3.60 (m,2H), 3.43 (m, 2H), 2.53-2.44 (m, 2H), 2.45 (s, 3H), 2.41 (s, 3H),2.32-2.16 (m, 2H), 1.80-1.17 (m, 15H), 1.02-0.93 (m, 2H), 0.96 (d, J=7.0Hz, 3H).

EXAMPLE 24(70)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.36 (d, J=8.4Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 4.30 (s, 2H), 4.02 (dd, J=7.8, 4.8 Hz,1H), 3.84 (m, 2H), 3.60 (m, 2H), 3.38 (m, 2H), 2.42 (s, 3H), 2.37 (s,3H), 2.35 (s, 3H), 2.52-2.18 (m, 4H), 1.90-1.32 (m, 7H), 0.96 (t, J=7.8Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 24(71)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.38 (d, J=8.4Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.06 (dd, J=7.5, 4.5 Hz,1H), 3.82 (m, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 2.43 (s, 3H), 2.38 (s,3H), 2.36 (s, 3H), 2.56-2.14 (m, 3H), 1.84-1.16 (m, 15H), 0.97 (t, J=7.2Hz, 3H), 0.97 (m, 2H).

EXAMPLE 24(72)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-chlorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.30 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.57 (d, J=9.0Hz, 2H), 7.49 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz,1H), 3.91-3.80 (m, 2H), 3.60 (m, 2H), 3.46 (m, 2H), 2.52 (m, 2H), 2.40(s, 3H), 2.39 (s, 3H), 2.27-2.15 (m, 2H), 1.86-1.81 (m, 1H), 1.76-1.51(m, 4H), 1.44-1.32 (m, 2H), 0.96 (t, J=7.0 Hz, 3H), 0.95 (d, J=6.0 Hz,3H), 0.94 (d, J=6.0 Hz, 3H).

EXAMPLE 24(73)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-chlorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.27 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.57 (d, J=8.5Hz, 2H), 7.48 (d, J=8.5 Hz, 2H), 4.31 (s, 2H), 4.04 (dd, J=7.8, 4.5 Hz,1H), 3.91-3.77 (m, 2H), 3.60 (m, 2H), 3.45 (m, 2H), 2.50 (m, 2H), 2.39(s, 6H), 2.27-2.14 (m, 2H), 1.80-1.51 (m, 9H), 1.44-1.17 (m, 6H),1.03-0.89 (m, 5H).

EXAMPLE 24(74)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-trifluoromethylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.23 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.87 (d, J=8.7Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz,1H), 3.93-3.78 (m, 2H), 3.60 (m, 2H), 3.43 (m, 2H), 2.50 (m, 2H), 2.45(s, 3H), 2.40 (s, 3H), 2.29-2.16 (m, 2H), 1.86-1.77 (m, 1H), 1.74-1.54(m, 4H), 1.44-1.34 (m, 2H), 0.96 (t, J=7.0 Hz, 3H), 0.95 (d, J=6.0 Hz,3H), 0.94 (d, J=6.0 Hz, 3H).

EXAMPLE 24(75)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-trifluoromethylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.37 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.87 (d, J=8.4Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 4.05 (dd, J=7.8, 4.5 Hz,1H), 3.92-3.78 (m, 2H), 3.60 (m, 2H), 3.45 (m, 2H), 2.50 (m, 2H), 2.45(s, 3H), 2.40 (s, 3H), 2.28-2.15 (m, 2H), 1.80-1.51 (m, 9H), 1.44-1.21(m, 6H), 1.03-0.93 (m, 5H).

EXAMPLE 24(76)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-diethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.70 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.53 (m,3H), 7.53-7.46 (m, 2H), 4.32 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H),3.95-3.79 (m, 2H), 3.65-3.58 (m, 2H), 3.50-3.38 (m, 2H), 2.85-2.75 (m,4H), 2.47 (br, 2H), 2.28-2.16 (m, 2H), 1.83-1.46 (m, 3H), 1.41-1.29 (m,4H), 0.98-0.91 (m, 15H).

EXAMPLE 24(77)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-diethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.67 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.53 (m,3H), 7.53-7.46 (m, 2H), 4.32 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H),3.95-3.79 (m, 2H), 3.70-3.55 (m, 2H), 3.47-3.31 (m, 2H), 2.91-2.75 (m,4H), 2.60-2.45 (m, 2H), 2.30-2.14 (m, 2H), 1.80-1.43 (m, 9H), 1.43-1.15(m, 8H), 0.98-0.91 (m, 9H).

EXAMPLE 24(78)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-phenylthiazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.62 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.03-8.00 (m,2H), 7.87 (s, 1H), 7.52-7.49 (m, 3H), 4.54 (s, 2H), 4.04 (dd, J=7.6, 4.8Hz, 1H), 4.04-3.87 (m, 2H), 3.70-3.58 (m, 2H), 3.51-3.39 (m, 2H),2.58-2.38 (m, 2H), 2.26-2.13 (m, 2H), 1.78-1.43 (m, 9H), 1.40-1.15 (m,6H), 1.10-0.90 (m, 5H).

EXAMPLE 24(79)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-phenylthiazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.02-8.01 (m,2H), 7.85 (s, 1H), 7.51-7.50 (m, 3H), 4.55 (s, 2H), 4.03-3.86 (m, 3H),3.68-3.59 (m, 2H), 3.45-3.36 (m, 2H), 2.50-2.34 (m, 2H), 2.29-2.16 (m,2H), 1.88-1.45 (m, 5H), 1.36 (q, J=7.2 Hz, 2H), 0.97-0.93 (m, 9H).

EXAMPLE 24(80)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(1,4-benzodioxan-2-yl)thiazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.88 (s, 1H),7.00 (m, 1H), 6.94-6.87 (m, 3H), 5.66 (dd, J=6.0, 2.7 Hz, 1H), 4.62 (dd,J=11.7, 2.7 Hz, 1H), 4.51 (s, 2H), 4.42 (dd, J=11.7, 6.0 Hz, 1H), 4.02(dd, J=7.5, 4.5 Hz, 1H), 3.88 (m, 2H), 3.58 (m, 2H), 3.40 (m, 2H),2.48-2.16 (m, 4H), 1.90-1.28 (m, 7H), 0.97 (t, J=7.5 Hz, 3H), 0.95 (d,J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 24(81)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-trifluoromethyl-2-(morpholin-1-yl)thiazol-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.78 (chloroform:methanol=10:1); NMR (CD₃OD): δ 4.63 (s, 2H),4.03 (dd, J=7.8, 4.8 Hz, 1H), 3.86-3.78 (m, 6H), 3.58 (m, 6H), 3.40 (m,2H), 2.44 (m, 2H), 2.22 (m, 2H), 1.88-1.32 (m, 8H), 0.97 (t, J=7.2 Hz,3H), 0.95 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 24(82)1-butyl-2,5-dioxo-3-(tetrahydropyran-4-ylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.31 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.60-7.46 (m,5H), 4.33 (s, 2H), 4.09 (dd, J=7.5, 4.5 Hz, 1H), 3.98-3.78 (m, 4H),3.68-3.56 (m, 2H), 3.50-3.36 (m, 4H), 2.58-2.16 (m, 4H), 2.40 (s, 3H),2.39 (s, 3H), 1.84-1.20 (m, 11H), 0.97 (t, J=7.2 Hz, 3H).

EXAMPLE 24(83)1-butyl-2,5-dioxo-3-(tetrahydropyran-4-ylmethyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06-6.92 (m,3H), 4.27 (s, 4H), 4.24 (s, 2H), 4.07 (dd, J=7.5, 4.5 Hz, 1H), 3.96-3.86(m, 2H), 3.84-3.68 (m, 2H), 3.52-3.36 (m, 6H), 2.44-2.10 (m, 4H),1.82-1.22 (m, 11H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 24(84)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-carboxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.58 (chloroform:methanol:acetic acid=20:2:1); NMR (CD₃OD): δ8.14 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 4.45 (s, 2H), 4.04 (dd,J=7.5, 4.5 Hz, 1H), 3.94-3.76 (m, 2H), 3.56-3.43 (m, 2H), 3.43-3.34 (m,2H), 2.50-2.31 (m, 2H), 2.28-2.08 (m, 2H), 1.84-1.12 (m, 15H), 1.06-0.90(m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 24(85)1-butyl-2,5-dioxo-3-(2-cyclohexylethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.56-7.45 (m,5H), 4.32 (s, 2H), 4.02 (t, J=4.8 Hz, 1H), 3.98-3.85 (m, 1H), 3.85-3.70(m, 1H), 3.65-3.56 (m, 2H), 3.56-3.42 (m, 1H), 3.42-3.30 (m, 1H),2.55-2.37 (m, 2H), 2.38 (s, 3H), 2.37 (s, 3H), 2.30-2.13 (m, 2H),1.92-1.78 (m, 2H), 1.78-1.60 (m, 5H), 1.60-1.48 (m, 2H), 1.48-1.32 (m,2H), 1.32-1.08 (m, 6H), 0.96 (t, J=7.2 Hz, 3H), 0.96-0.85 (m, 2H).

EXAMPLE 24(86)1-butyl-2,5-dioxo-3-(2-cyclohexylethyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.05 (d, J=2.1Hz, 1H), 6.98 (dd, J=8.1, 2.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.26 (s,4H), 4.23 (s, 2H), 4.03 (t, J=4.8 Hz, 1H), 3.90-3.79 (m, 1H), 3.76-3.62(m, 1H), 3.50-3.38 (m, 3H), 3.38-3.30 (m, 1H), 2.43-2.06 (m, 4H),1.92-1.78 (m, 2H), 1.78-1.60 (m, 5H), 1.60-1.45 (m, 2H), 1.42-1.30 (m,2H), 1.30-1.08 (m, 6H), 0.95 (t, J=7.2 Hz, 3H), 0.97-0.88 (m, 2H).

EXAMPLE 24(87)(3R)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.48 (m,5H), 4.33 (s, 2H), 4.06 (dd, J=7.5, 4.5 Hz, 1H), 3.95-3.78 (m, 2H),3.68-3.58 (m, 2H), 3.50-3.40 (m, 2H), 2.62-2.45 (m, 2H), 2.42 (s, 3H),2.40 (s, 3H), 2.30-2.12 (m, 2H), 1.82-1.12 (m, 15H), 0.97 (t, J=7.2 Hz,3H), 0.97 (m, 2H).

EXAMPLE 24(88)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methyl-2-phenylthiazol-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.75 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.98-7.95 (m,2H), 7.55-7.50 (m, 3H), 4.69 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz, 1H),3.98-3.78 (m, 2H), 3.65-3.56 (m, 2H), 3.50-3.40 (m, 2H), 2.58 (s, 3H),2.60-2.48 (m, 2H), 2.27-2.14 (m, 2H), 1.88-1.48 (m, 5H), 1.48-1.30 (m,2H), 0.97-0.93 (m, 9H).

EXAMPLE 24(89)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(thiophen-1-yl)thiazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.81 (s, 1H),7.67 (d, J=3.9 Hz, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.14 (dd, J=5.4, 3.9 Hz,1H), 4.49 (s, 2H), 4.00 (dd, J=7.8, 4.5 Hz, 1H), 3.98-3.82 (m, 2H),3.62-3.55 (m, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.58-2.40 (m, 2H), 2.28-2.10(m, 2H), 1.86-1.42 (m, 5H), 1.46-1.30 (m, 2H), 0.97-0.93 (m, 9H).

EXAMPLE 24(90)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(pyridin-4-yl)thiazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.98 (d, J=6.9Hz, 2H), 8.71 (d, J=6.9 Hz, 2H), 8.37 (s, 1H), 4.66 (s, 2H), 4.01 (dd,J=7.8, 4.8 Hz, 1H), 4.00-3.87 (m, 2H), 3.70-3.59 (m, 2H), 3.50 (t, J=7.8Hz, 2H), 2.72-2.58 (m, 2H), 2.25-2.08 (m, 2H), 1.88-1.46 (m, 5H),1.46-1.35 (m, 2H), 0.97-0.92 (m, 9H).

EXAMPLE 24(91)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,4-dimethoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.23 (s, 1H),7.09 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.29 (s, 2H), 4.04 (dd,J=7.5, 4.8 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.88-3.64 (m, 2H),3.56-3.38 (m, 4H), 2.58-2.37 (m, 2H), 2.24-2.08 (m, 2H), 1.82-1.10 (m,15H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 24(92)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.31 (chloroform:methanol=10:1); NMR (CD₃OD): δ 6.74 (d, J=1.8Hz, 2H), 6.60 (t, J=1.8 Hz, 1H), 4.28 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz,1H), 3.86-3.70 (m, 2H), 3.83 (s, 6H), 3.58-3.36 (m, 4H), 2.52-2.36 (m,2H), 2.24-2.08 (m, 2H), 1.82-1.10 (m, 15H), 0.96 (t, J=7.2 Hz, 3H), 0.96(m, 2H).

EXAMPLE 24(93)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(5-(pyridin-2-yl)furan-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.76 (dd, J=5.4,1.5 Hz, 1H), 8.51 (ddd, J=8.1, 7.5, 1.5 Hz, 1H), 8.39 (d, J=7.5 Hz, 1H),7.85 (dd, J=8.1, 5.4 Hz, 1H), 7.61 (d, J=3.6 Hz, 1H), 7.08 (d, J=3.6 Hz,1H), 4.63 (s, 2H), 4.00 (dd, J=7.8, 4.5 Hz, 1H), 3.98-3.81 (m, 2H),3.65-3.55 (m, 2H), 3.49 (t, J=8.1 Hz, 2H), 2.72-2.55 (m, 2H), 2.28-2.10(m, 2H), 1.90-1.27 (m, 7H), 1.00-0.89 (m, 9H).

EXAMPLE 24(94)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(5-(pyridin-3-yl)furan-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD): δ 9.34 (d, J=1.8Hz, 1H), 8.94 (dd, J=8.1, 1.8 Hz, 1H), 8.75 (d, J=5.4 Hz, 1H), 8.10 (dd,J=8.1, 5.4 Hz, 1H), 7.34 (d, J=3.6 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 4.57(s, 2H), 4.00 (dd, J=7.8, 4.5 Hz, 1H), 3.98-3.77 (m, 2H), 3.63-3.43 (m,4H), 2.73-2.55 (m, 2H), 2.28-2.09 (m, 2H), 1.89-1.27 (m, 7H), 1.00-0.89(m, 9H).

EXAMPLE 24(95)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(3,5-dimethylpyrazol-1-yl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.52 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.94 (d, J=8.1Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 6.51 (s, 1H), 4.49 (s, 2H), 4.01 (dd,J=7.8, 4.5 Hz, 1H), 3.85-3.76 (m, 2H), 3.58-3.48 (m, 4H), 2.72-2.58 (m,2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.23-2.06 (m, 2H), 1.88-1.45 (m, 5H),1.45-1.34 (m, 2H), 0.97-0.92 (m, 9H).

EXAMPLE 24(96)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(5-chloropyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.54 (bs, 1H),8.45 (bs, 1H), 7.87 (bs, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz,2H), 4.39 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.90-3.73 (m, 2H),3.56-3.40 (m, 4H), 2.64-2.46 (m, 2H), 2.24-2.09 (m, 2H), 1.86-1.42 (m,5H), 1.42-1.30 (m, 2H), 0.97-0.92 (m, 9H).

EXAMPLE 24(97)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyrimidin-2-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.62 (d, J=4.8Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.26 (t, J=4.8Hz, 1H), 4.40 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.93-3.72 (m, 2H),3.60-3.35 (m, 4H), 2.58-2.40 (m, 2H), 2.28-2.07 (m, 2H), 1.90-1.45 (m,5H), 1.45-1.36 (m, 2H), 0.98-0.90 (m, 9H).

EXAMPLE 24(98)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.76 (d, J=2.7Hz, 1H), 8.63 (d, J=5.7 Hz, 1H), 8.28 (dd, J=8.7, 2.7 Hz, 1H), 8.07 (dd,J=8.7, 5.7 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.41(s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.93-3.72 (m, 2H), 3.58-3.40 (m,4H), 2.68-2.48 (m, 2H), 2.26-2.06 (m, 2H), 1.90-1.46 (m, 5H), 1.46-1.30(m, 2H), 0.98-0.91 (m, 9H).

EXAMPLE 24(99)1-(2-butynyl)-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.28 (chloroform:methanol=19:1); NMR (CD₃OD): δ 7.39-7.29 (m,4H), 4.31 (s, 2H), 4.27-4.20 (m, 2H), 4.06 (dd, J=7.5, 4.8 Hz, 1H), 3.84(m, 2H), 3.62 (m, 2H), 2.59 (m, 2H), 2.42 (s, 3H), 2.37 (s, 3H), 2.34(s, 3H), 2.28 (m, 2H), 1.92-1.60 (m, 6H), 0.96 (d, J=6.3 Hz, 3H), 0.95(d, J=6.3 Hz, 3H).

EXAMPLE 24(100)(3R)-1-(2-butynyl)-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.29 (chloroform:methanol=19:1); NMR (CD₃OD): δ 7.59-7.43 (m,5H), 4.31 (s, 2H), 4.25 (q, J=2.1 Hz, 2H), 4.09 (dd, J=7.2, 4.8 Hz, 1H),3.85 (dt, J=3.0, 12.3 Hz, 2H), 3.68-3.56 (m, 2H), 2.61 (m, 2H), 2.38 (s,3H), 2.37 (s, 3H), 2.26 (m, 2H), 1.83-1.43 (m, 8H), 1.75 (t, J=2.1 Hz,3H), 1.38-1.12 (m, 3H), 0.96 (m, 2H).

EXAMPLE 24(101)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-hydroxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=9.0Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0Hz, 2H), 4.30 (s, 2H), 4.00 (dd, J=7.5, 4.8 Hz, 1H), 3.86-3.70 (m, 2H),3.52-3.34 (m, 4H), 2.48-2.30 (m, 2H), 2.28-2.10 (m, 2H), 1.88-1.44 (m,5H), 1.44-1.28 (m, 2H), 0.97-0.92 (m, 9H).

EXAMPLE 24(102)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridin-2-yl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.89 (d, J=7.8Hz, 1H), 8.70 (t, J=7.8 Hz, 1H), 8.43 (d, J=8.4 Hz, 1H), 8.10-8.06 (m,3H), 7.98 (d, J=8.7 Hz, 2H), 4.51 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H),3.96-3.78 (m, 2H), 3.56-3.45 (m, 4H), 2.72-2.58 (m, 2H), 2.24-2.08 (m,2H), 1.84-1.44 (m, 5H), 1.44-1.34 (m, 2H), 0.97-0.92 (m, 9H).

EXAMPLE 24(103)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridin-3-yl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 9.24 (s, 1H),8.98 (d, J=8.4 Hz, 1H), 8.88 (d, J=8.4 Hz, 1H), 8.21 (dd, J=8.4, 5.7 Hz,1H), 7.96 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 4.47 (s, 2H), 4.01(dd, J=7.5, 4.8 Hz, 1H), 3.96-3.75 (m, 2H), 3.58-3.44 (m, 4H), 2.64-2.50(m, 2H), 2.25-2.08 (m, 2H), 1.88-1.48 (m, 5H), 1.48-1.32 (m, 2H),0.97-0.92 (m, 9H).

EXAMPLE 24(104)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-carboxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.27 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.19 (d, J=8.4Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.96-3.74 (m, 2H), 3.66-3.55 (m, 2H), 3.48-3.36 (m, 2H), 2.58-2.40(m, 2H), 2.45 (s, 3H), 2.40 (s, 3H), 2.32-2.14 (m, 2H), 1.90-1.46 (m,5H), 1.46-1.30 (m, 2H), 0.99-0.95 (m, 9H).

EXAMPLE 24(105)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyrazin-2-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.48 (chloroform:methanol=20:1); NMR (CD₃OD): δ 8.47 (d, J=1.5Hz, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.13 (dd, J=2.7, 1.5 Hz, 1H), 7.65 (d,J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.40 (s, 2H), 4.02 (dd, J=7.5,4.5 Hz, 1H), 3.94-3.73 (m, 2H), 3.58-3.46 (m, 2H), 3.44-3.34 (m, 2H),2.52-2.34 (m, 2H), 2.30-2.10 (m, 2H), 1.90-1.43 (m, 5H), 1.43-1.26 (m,2H), 0.99-0.90 (m, 9H).

EXAMPLE 24(106)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-carboxyphenyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.20 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.11 (d, J=8.4Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 4.43 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.96-3.74 (m, 2H),3.58-3.36 (m, 4H), 2.55-2.38 (m, 2H), 2.28-2.10 (m, 2H), 1.88-1.44 (m,5H), 1.44-1.30 (m, 2H), 0.97-0.92 (m, 9H).

EXAMPLE 24(107)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridin-4-yl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.91 (d, J=6.9Hz, 2H), 8.45 (d, J=6.9 Hz, 2H), 8.11 (d, J=7.8 Hz, 2H), 7.91 (d, J=7.8Hz, 2H), 4.49 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.96-3.78 (m, 2H),3.58-3.40 (m, 4H), 2.64-2.48 (m, 2H), 2.26-2.08 (m, 2H), 1.90-1.28 (m,7H), 0.96-0.93 (m, 9H).

EXAMPLE 24(108)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridin-2-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.44-8.15 (m,2H), 7.82 (d, J=7.2 Hz, 2H), 7.60-7.40 (m, 1H), 7.42 (d, J=7.2 Hz, 2H),7.27-7.24 (m, 1H), 4.43 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.92-3.70(m, 2H), 3.58-3.40 (m, 4H), 2.64-2.42 (m, 2H), 2.28-2.06 (m, 2H),1.92-1.28 (m, 7H), 0.97-0.94 (m, 9H).

EXAMPLE 24(109)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(naphthalen-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.71 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.08-7.93 (m,4H), 7.64-7.57 (m, 3H), 4.54 (s, 2H), 4.04 (dd, J=7.5, 4.8 Hz, 1H),3.96-3.80 (m, 2H), 3.60-3.44 (m, 2H), 3.42-3.36 (m, 2H), 2.42-2.08 (m,4H), 1.82-1.16 (m, 15H), 0.95 (t, J=7.5 Hz, 3H), 0.95 (m, 2H).

EXAMPLE 24(110)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(6-methoxynaphthalen-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.75 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.98 (s, 1H),7.91 (d, J=8.7 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H),7.31 (d, J=2.4 Hz, 1H), 7.22 (dd, J=8.7, 2.4 Hz, 1H), 4.48 (s, 2H), 4.04(dd, J=7.8, 4.8 Hz, 1H), 3.94-3.78 (m, 2H), 3.93 (s, 3H), 3.58-3.44 (m,2H), 3.42-3.36 (m, 2H), 2.48-2.30 (m, 2H), 2.24-2.08 (m, 2H), 1.82-1.10(m, 15H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (m, 2H).

EXAMPLE 24(111)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.27 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.03 (d, J=8.7Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.37 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz, 1H), 3.90-3.70 (m, 2H),3.56-3.36 (m, 4H), 2.56-2.38 (m, 2H), 2.25-2.10 (m, 2H), 1.84-1.44 (m,5H), 1.44-1.39 (m, 2H), 0.98-0.93 (m, 9H).

EXAMPLE 24(112)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(5-(pyridin-4-yl)furan-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.80 (d, J=6.9Hz, 2H), 8.39 (d, J=6.9 Hz, 2H), 7.69 (d, J=3.6 Hz, 1H), 7.08 (d, J=3.6Hz, 1H), 4.62 (s, 2H), 4.00 (dd, J=7.8, 4.5, Hz, 1H), 3.99-3.79 (m, 2H),3.65-3.43 (m, 4H), 2.72-2.54 (m, 2H), 2.30-2.10 (m, 2H), 1.88-1.26 (m,7H), 1.00-0.84 (m, 9H).

EXAMPLE 24(113)1-butyl-2,5-dioxo-3-cyclopentylmethyl-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.66 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=8.5Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.05 (m, 4H),4.34 (s, 2H), 4.00 (t, J=6.0 Hz, 1H), 3.82 (m, 2H), 3.49 (m, 2H), 3.39(m, 2H), 2.37 (m, 2H), 2.17 (m, 2H), 1.96 (m, 1H), 1.81 (m, 4H), 1.58(m, 6H), 1.38 (m, 2H), 1.17 (m, 2H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 24(114)(3R)-1-butyl-2,5-dioxo-3-(2,2-dimethylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.52 (d, J=9.0Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.04 (m, 4H),4.33 (s, 2H), 4.01 (dd, J=7.2, 3.3 Hz, 1H), 3.82 (m, 1H), 3.71 (m, 1H),3.50 (m, 2H), 3.43 (m, 2H), 2.38 (m, 2H), 2.24 (m, 2H), 2.00 (dd,J=14.0, 3.3 Hz, 1H), 1.55 (dd, J=14.0, 7.2 Hz, 1H), 1.50 (m, 2H), 1.36(m, 2H), 0.99 (s, 9H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 24(115)(3S)-1-butyl-2,5-dioxo-3-(2,2-dimethylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.52 (d, J=9.0Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.04 (m, 4H),4.33 (s, 2H), 4.01 (dd, J=7.2, 3.3 Hz, 1H), 3.82 (m, 1H), 3.71 (m, 1H),3.50 (m, 2H), 3.43 (m, 2H), 2.38 (m, 2H), 2.24 (m, 2H), 2.00 (dd,J=14.0, 3.3 Hz, 1H), 1.55 (dd, J=14.0, 7.2 Hz, 1H), 1.50 (m, 2H), 1.36(m, 2H), 0.99 (s, 9H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 24(116)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-nitrophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.68 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.33 (d,J=8.7Hz, 2H), 7.78 (d, J=8.7Hz, 2H), 4.49 (s, 2H), 4.03 (dd, J=7.5,4.5Hz, 1H), 3.93-3.76 (m, 2H), 3.55-3.43 (m, 2H), 3.40-3.31 (m, 2H),2.45-2.28 (m, 2H), 2.27-2.08 (m, 2H), 1.83-1.14 (m, 15H), 1.04-0.86 (m,5H).

EXAMPLE 24(117)(3R)-1-(tetrahydrofuran-2-ylmethyl)-2,5-dioxo-3-phenylmethyl-9-(4-phenylbutyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CDCl₃): δ 7.38-7.14 (m,10H), 6.00-5.75 (m, 1H), 4.40-4.15 (m, 2H), 3.92-3.58 (m, 3H), 3.58-2.25(m, 13H), 2.18-1.45 (m, 10H).

EXAMPLE 24(118)(3S)-1-(tetrahydrofuran-2-ylmethyl)-2,5-dioxo-3-phenylmethyl-9-(4-phenylbutyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CDCl₃): δ 7.40-7.15 (m,10H), 6.05-5.80 (m, 1H), 4.40-4.10 (m, 2H), 3.90-3.55 (m, 3H), 3.55-2.20(m, 13H), 2.18-1.45 (m, 10H).

EXAMPLE 24(119)(3S)-1-propyl-2,5-dioxo-3-(3-(benzyloxycarbonylamino)propyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.32 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.20 (m,10H), 5.06 (s, 2H), 4.09 (dd, J=5.2, 4.6 Hz, 1H), 4.00-3.70 (m, 2H),3.70-3.55 (m, 2H), 3.50-3.30 (m, 4H), 3.20-3.00 (m, 4H), 2.65-2.35 (m,2H), 2.30-2.10 (m, 2H), 2.00-1.75 (m, 2H), 1.70-1.40 (m, 4H), 0.96 (t,J=7.4 Hz, 3H).

EXAMPLE 251-butyl-2,5-dioxo-3-(carboxymethyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

To a solution of the compound prepared in Example 24(11) (173 mg) inmethanol (5 mL) was added 2N aqueous solution of sodium hydroxide (2ml). The reaction mixture was stirred for 3 hours at room temperature.The reaction mixture was acidified to pH 4 by adding 2N hydrochloricacid, and was extracted with ethyl acetate. The extract was washed witha saturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate and concentrated. The obtained residue was dissolved in1,4-dioxane, and 4N hydrogen chloride-1,4-dioxane solution was addedthereto. The reaction mixture was concentrated. The obtained residue waswashed with diethyl ether and dried to give the compound of the presentinvention (127 mg) having the following physical data.

TLC: Rf 0.51 (chloroform:methanol:acetic acid=20:4:1); NMR (CD₃OD): δ7.55-7.53 (m, 2H), 7.42-7.36 (m, 2H), 7.20-7.15 (m, 1H), 7.07-7.02 (m,4H), 4.33 (s, 2H), 4.27 (t, J=4.5 Hz, 1H), 3.96-3.90 (m, 1H), 3.72-3.66(m, 1H), 3.54-3.38 (m, 4H), 2.97 (dd, J=18.0, 4.8 Hz, 1H), 2.79 (dd,J=18.0, 4.8 Hz, 1H), 2.50-2.36 (m, 3H), 2.27-2.16 (m, 1H), 1.62-1.48 (m,2H), 1.41-1.30 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 26(1) TO 26(3)

By the same procedure as described in Reference Example 3→ReferenceExample 4 using Resin (3) prepared in Reference Example 2 andN-allyloxycarbonyl-4-piperidone, using the corresponding compoundsrespectively instead of n-propylamine and N-(t-butyloxycarbonyl)leucine,and furthermore by the same procedure as described in Reference Example5→Reference Example 6→Example 1 using the corresponding compound insteadof 3,5-dimethyl-1-phenyl-4-formylpyrazole, and furthermore by the sameprocedure as described in Example 25 because of acetylation of a part ofhydroxy group, the following compounds of the present invention wereobtained.

EXAMPLE 26(1)1-(3-hydroxybutyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54 (d, J=8.5Hz, 2H), 7.39 (t, J=7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.04 (m, 4H),4.33 (s, 2H), 4.02 (m, 1H), 3.80 (m, 3H), 3.51 (m, 4H), 2.46 (m, 2H),2.19 (m, 2H), 1.85-1.57 (m, 5H), 1.17 (d, J=6.0 Hz, 3H), 0.94 (d, J=9.0Hz, 6H).

EXAMPLE 26(2)1-(3-hydroxypropyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d, J=8.5Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.04 (m, 4H),4.34 (s, 2H), 4.02 (dd, J=7.5, 4.0 Hz, 1H), 3.80 (m, 2H), 3.60 (t, J=6.0Hz, 2H), 3.48 (m, 4H), 2.40 (m, 2H), 2.20 (m, 2H), 1.82-1.58 (m, 5H),0.94 (d, J=6.0 Hz, 3H), 0.93 (d, J=6.0 Hz, 3H).

EXAMPLE 26(3)1-(2-hydroxybutyl)-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10-7.00(m, 4H), 4.32 (s, 2H), 4.03 (dd, J=8.1, 4.8 Hz, 1H), 3.96-3.41 (m, 6H),3.27-3.14 (m, 1H), 2.68-2.53 (m, 1H), 2.37-2.26 (m, 3H), 1.94-1.24 (m,5H), 1.08-0.82 (m, 9H).

EXAMPLE 271-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-aminophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

Under an atmosphere of argon, to a solution of the compound prepared inExample 24(116) (50 mg) in methanol was added 5% palladium on carbon (10mg). Under an atmosphere of hydrogen, the reaction mixture was stirredfor 20 minutes at room temperature. The reaction mixture was filtratedthrough Celite (brand name). The filtrate was concentrated. The residuewas purified by column chromatography on silica gel(chloroform:methanol=50:1→30:1→20:1). The obtained compound wasdissolved in methanol, and 4N-hydrogen chloride/ethyl acetate solutionwas added thereto. It was concentrated. The obtained residue was washedwith diethyl ether and dried to give the compound of the presentinvention (34 mg) having the following physical data.

TLC: Rf 0.21 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.80 (d, J=8.4Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 4.41 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.86-3.74 (m, 2H), 3.52-3.45 (m, 4H), 2.65-2.52 (m, 2H), 2.24-2.08(m, 2H), 1.80-1.16 (m, 15H), 0.94 (t, J=7.5 Hz, 3H), 0.94 (m, 2H).

EXAMPLE 281-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-((4-methylphenyl)sulfonylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

To a solution of the compound prepared in Example 28 (33 mg) in pyridine(2 ml) was added p-toluenesulfonyl chloride (21 mg). The reactionmixture was stirred for 27 hours at room temperature. The reactionmixture was concentrated, and saturated aqueous solution of sodiumhydrogen carbonate was added thereto. It was extracted with ethylacetate. The extract was washed with saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate, and concentrated.The residue was purified by column chromatography on silica gel(chloroform:methanol=10:1). The obtained compound was dissolved inmethanol, and 4N hydrogen chloride/ethyl acetate solution was addedthereto, and it was concentrated. The residue was washed with diethylether and dried to give the compound of the present invention (27 mg)having the following physical data.

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.70 (d, J=8.4Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 4.25 (s, 2H), 4.03 (dd, J=7.2, 4.5 Hz, 1H), 3.78 (m, 2H), 3.42(m, 4H), 2.42-2.06 (m, 4H), 2.37 (s, 3H), 1.82-1.10 (m, 15H), 0.95 (t,J=7.2 Hz, 3H), 0.95 (m, 2H).

EXAMPLE 28(1)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(phenylcarbonylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 28 using benzoyl chlorideinstead of p-toluenesulfonyl chloride, the compound of the presentinvention having the following physical data was obtained.

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.93 (d, J=8.4Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.61-7.50 (m, 5H), 4.34 (s, 2H), 4.05(dd, J=7.8, 4.5 Hz, 1H), 3.80 (m, 2H), 3.42 (m, 4H), 2.24 (m, 4H),1.82-1.16 (m, 15H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 29(3S)-1-butyl-2,5-dioxo-3-benzyloxymethyl-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Reference Example 3→ReferenceExample 6→Example 1 using Resin (3) prepared in Reference Example 2 andN-benzyloxycarbonyl-4-piperidone,O-benzyl-N-(t-butyloxycarbonyl)-L-serine, the compound of the presentinvention having the following physical data was obtained.

TLC: Rf 0.66 (chloroform:methanol=20:1); NMR (CDCl₃): δ 7.40-7.25 (m,10H), 6.09 (brs, 1H), 5.15 (s, 2H), 4.54 (s, 2H), 4.20-3.98 (br, 2H),4.18 (dd, J=8.4, 3.6 Hz, 1H), 3.93 (dd, J=9.3, 3.6 Hz, 1H), 3.80-3.56(br, 1H), 3.66 (dd, J=9.3, 8.4, Hz, 1H), 3.45-3.12 (m, 3H), 2.02-1.75(m, 4H), 1.57-1.39 (m, 2H), 1.38-1.20 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

EXAMPLE 30(3S)-1-butyl-2,5-dioxo-3-hydroxymethyl-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Example 29 (245 mg) indichloromethane (5 ml) was added a 1M solution of tribromoborane indichloromethane (1.4 ml) at −40° C., and it was stirred for 3 hours at−20° C. To the reaction mixture were added water and saturated aqueoussolution of sodium hydrogen carbonate, and it was extracted with ethylacetate. The extract was washed with water and saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andconcentrated. The residue was purified by column chromatography onsilica gel (chloroform:methanol=30:1) to give the compound of thepresent invention (173 mg) having the following physical data.

TLC: Rf 0.29 (chloroform:methanol=20:1); NMR (CDCl₃): δ 7.42-7.27 (m,5H), 6.26-6.15 (br, 1H), 5.16 (s, 2H), 4.26-4.00 (m, 2H), 3.98-3.82 (m,2H), 3.84-3.60 (br, 1H), 3.43-3.13 (m, 4H), 2.80-2.68 (br, 1H),2.05-1.75 (m, 4H), 1.58-1.40 (m, 2H), 1.40-1.20 (m, 2H), 0.92 (t, J=7.5Hz, 3H).

EXAMPLE 31(3S)-1-butyl-2,5-dioxo-3-hydroxymethyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 9 using the compoundprepared in Example 30, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.21 (chloroform:methanol:acetic acid=20:4:1); NMR (d₆-DMSO): δ7.83 (brs, 1H), 5.10-4.90 (br, 1H), 3.88-3.78 (m, 1H), 3.76-3.65 (m,1H), 3.58-3.48 (m, 1H), 3.28-3.18 (m, 1H), 3.18-3.04 (m, 3H), 2.88-2.75(m, 2H), 1.94-1.83 (m, 1H), 1.83-1.64 (m, 3H), 1.56-1.42 (m, 1H),1.42-1.20 (m, 3H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 32(1)(3S)-1-butyl-2,5-dioxo-3-hydroxymethyl-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 10 using4-phenyloxybenzaldehyde and the compound prepared in Example 31, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=8.7Hz, 2H), 7.43-7.35 (m, 2H), 7.22-7.14 (m, 1H), 7.06 (d, J=8.7 Hz, 2H),7.06-7.00 (m, 2H), 4.33 (s, 2H), 4.03-3.90 (m, 3H), 3.79-3.66 (m, 1H),3.65 (dd, J=10.5, 2.4 Hz, 1H), 3.61-3.42 (m, 3H), 3.30-3.18 (m, 1H),2.50-2.24 (m, 3H), 2.24-2.12 (m, 1H), 1.76-1.58 (m, 1H), 1.54-1.26 (m,3H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 32(2)(3S)-1-butyl-2,5-dioxo-3-hydroxymethyl-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 10 using1-phenyl-3,5-dimethyl-4-formylpyrazole and the compound prepared inExample 31, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.46 (m,5H), 4.32 (s, 2H), 4.08-3.92 (m, 3H), 3.83-3.70 (m, 1H), 3.66 (dd,J=10.5, 2.4 Hz, 1H), 3.66-3.52 (m, 3H), 3.40-3.25 (m, 1H), 2.64-2.50 (m,1H), 2.50-2.40 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.28-2.15 (m, 1H),1.80-1.58 (m, 1H), 1.58-1.30 (m, 3H), 0.96 (t, J=7.5 Hz, 3H).

REFERENCE EXAMPLE 11 Preparation of Compound (7)

By the same procedure as described in Reference Example 3→ReferenceExample 4 using Resin (3) prepared in Reference Example 2 andN-allyloxycarbonyl-4-piperidone, n-butylamine andN-(t-butyloxycarbonyl)leucine, and furthermore by the same procedure asdescribed in Reference Example 5 using 4-hydroxybenzaldehyde instead of3,5-dimethyl-1-phenyl-4-formylpyrazole, compound (7) was obtained.

REFERENCE EXAMPLE 12 Preparation of Compound (8)

To a suspension of the compound prepared in Reference Example 11 (60 mg)in dichloromethane (2 ml) were added triphenylphosphine (80 mg), 1Mcyclopentanol-dichloromethane solution (0.302 ml) anddiethylazodicarboxylate (0.137 ml). The reaction mixture was stirred for18 hours at room temperature. The reaction solution was filtrated. Theobtained resin was washed with dichloromethane (2 ml×4), methanol (2ml×3), and dichloromethane (3 ml×4) to give compound (8).

EXAMPLE 331-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-cyclopentyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Reference Example 6→Example 1using the compound prepared in Reference Example 12, the compound of thepresent invention having the following physical data was obtained.

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.41 (d, J=8.7Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 4.83 (m, 1H), 4.25 (brs, 2H), 4.00 (dd,J=7.8, 4.5 Hz, 1H), 3.86-3.65 (m, 2H), 3.53-3.27 (m, 4H), 2.40-2.06 (m,4H), 2.02-1.43 (m, 13H), 1.43-1.24 (m, 2H), 1.01-0.90 (m, 9H).

EXAMPLE 33(1) TO 33(6)

By the same procedure as described in Reference Example 11 using thecorresponding compounds instead of n-butylamine andN-(t-butyloxycarbonyl)leucine, and by the same procedure as described inReference Example 12→Example 33 using the corresponding compoundsinstead of cyclopentanol, the following compounds of the presentinvention were obtained.

EXAMPLE 33(1)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(2-diethylaminoethyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.54 (chloroform:methanol:28% NH₄OH=80:10:1); NMR (CD₃OD): δ7.57 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H), 4.40 (t, J=4.8 Hz, 2H),4.30 (s, 2H), 4.03 (dd, J=7.5, 5.1 Hz, 1H), 3.84-3.67 (m, 2H), 3.63 (t,J=4.8 Hz, 2H), 3.50-3.40 (m, 4H), 3.40-3.31 (m, 4H), 2.58-2.41 (m, 2H),2.23-2.04 (m, 2H), 1.82-1.42 (m, 10H), 1.41-1.12 (m, 11H), 1.04-0.87 (m,5H).

EXAMPLE 33(2)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(2-dimethylaminoethyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.46 (chloroform:methanol:28% NH₄OH=80:10:1); NMR (CD₃OD): δ7.57 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H), 4.39 (t, J=4.8 Hz, 2H),4.30 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.84-3.67 (m, 2H), 3.61 (t,J=4.8 Hz, 2H), 3.50-3.38 (m, 4H), 2.98 (s, 6H), 2.59-2.42 (m, 2H),2.24-2.03 (m, 2H), 1.83-1.12 (m, 15H), 1.04-0.86 (m, 5H).

EXAMPLE 33(3)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-propyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.43 (d, J=8.7Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 4.27 (brs, 2H), 4.03 (dd, J=7.5, 4.5Hz, 1H), 3.96 (t, J=6.6 Hz, 2H), 3.85-3.67 (m, 2H), 3.53-3.33 (m, 4H),2.45-2.27 (m, 2H), 2.26-2.07 (m, 2H), 1.86-1.14 (m, 17H), 1.03 (t, J=7.2Hz, 3H), 1.00-0.89 (m, 5H).

EXAMPLE 33(4)1-(thiophen-2-ylmethyl)-2,5-dioxo-3-cyclohexylmethyl-9-(4-cyclopropylmethyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.42 (d, J=8.7Hz, 2H), 7.27 (dd, J=5.4, 0.9 Hz, 1H), 7.06-6.97 (m, 3H), 6.91 (dd,J=5.4, 3.6 Hz, 1H), 4.95-4.85 (m, 2H), 4.27 (brs, 2H), 4.14 (dd, J=7.5,4.5 Hz, 1H), 3.84 (d, J=6.6 Hz, 2H), 3.84-3.66 (m, 2H), 3.51-3.39 (m,2H), 2.59-2.36 (m, 2H), 2.24-2.07 (m, 2H), 1.84-1.44 (m, 8H), 1.35-1.12(m, 4H), 1.04-0.85 (m, 2H), 0.66-0.57 (m, 2H), 0.38-0.31 (m, 2H).

EXAMPLE 33(5)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-cyclopropylmethyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.42 (d, J=8.4Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 4.26 (brs, 2H), 4.03 (dd, J=7.8, 4.8Hz, 1H), 3.84 (d, J=6.9 Hz, 2H), 3.83-3.66 (m, 2H), 3.51-3.33 (m, 4H),2.44-2.26 (m, 2H), 2.25-2.06 (m, 2H), 1.82-1.12 (m, 16H), 1.04-0.86 (m,5H), 0.66-0.57 (m, 2H), 0.38-0.31 (m, 2H).

EXAMPLE 33(6)1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-cyclopropylmethyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.42 (d, J=8.7Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 4.26 (brs, 2H), 4.00 (dd, J=7.8, 4.5Hz, 1H), 3.84 (d, J=6.9 Hz, 2H), 3.84-3.66 (m, 2H), 3.50-3.33 (m, 4H),2.43-2.26 (m, 2H), 2.26-2.08 (m, 2H), 1.89-1.43 (m, 5H), 1.43-1.17 (m,3H), 1.00-0.88 (m, 9H), 0.66-0.58 (m, 2H), 0.38-0.31 (m, 2H).

EXAMPLE 341-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(dimethylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 10 using4-dimethylaminobenzaldehyde and the compound prepared in Example 9(1),the compound of the present invention having the following physical datawas obtained.

TLC: Rf 0.26 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.78 (d, J=8.7Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 4.39 (s, 2H), 4.03 (dd, J=7.5, 4.8, Hz,1H), 3.90-3.70 (m, 2H), 3.52-3.40 (m, 4H), 3.26 (s, 6H), 2.64-2.47 (m,2H), 2.24-2.04 (m, 2H), 1.82-1.12 (m, 15H), 1.04-0.88 (m, 5H).

EXAMPLE 34(1)1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(diethylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 34 using4-diethylaminobenzaldehyde instead of 4-dimethylaminobenzaldehyde, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.28 (chloroform:methanol:acetic acid=10:1); NMR (CD₃OD): δ7.94-7.78 (m, 2H), 7.72-7.52 (m, 2H), 4.43 (s, 2H), 4.03 (dd, J=7.5,4.8, Hz, 1H), 3.92-3.73 (m, 2H), 3.73-3.60 (m, 4H), 3.54-3.40 (m, 4H),2.63-2.45 (m, 2H), 2.25-2.05 (m, 2H), 1.82-1.10 (m, 21H), 1.04-0.86 (m,5H).

EXAMPLE 35(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Reference Example 3→ReferenceExample 6→Example 1 using Resin (3) prepared in Reference Example 2,N-benzyloxycarbonyl-4-piperidone, n-butylamine andN-(t-butyloxycarbonyl)-L-leucine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.67 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.35 (m, 5H),6.50 (brs, 1H), 5.15 (s, 2H), 4.08 (m, 2H), 3.96 (m, 1H), 3.62 (brs,1H), 3.44 (brs, 1H), 3.26 (m, 2H), 1.95-1.76 (m, 4H), 1.61-1.45 (m, 5H),1.31 (m, 2H), 0.96 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 0.91 (t,J=7.2 Hz, 3H).

EXAMPLE 36

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 9 using the compoundprepared in Example 35, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.18 (chloroform:methanol=4:1); NMR (CD₃OD): δ 4.02 (dd, J=7.8,4.6 Hz, 1H), 3.80 (dd, J=12.5, 4.0 Hz, 1H), 3.72 (dd, J=12.5, 4.0 Hz,1H), 3.39 (m, 4H), 2.34-2.09 (m, 4H), 1.88-1.50 (m, 5H), 1.37 (m, 2H),0.96 (t, J=7.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H).

EXAMPLE 37(1) TO 37(88)

By the same procedure as described in Example 10 using the compoundprepared in Example 36 and the corresponding aldehyde derivatives, thefollowing compounds of the present invention were obtained.

EXAMPLE 37(1)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(5-(3-methyl-4-chlorophenyl)-1-(4-methylphenylmethyl)pyrazol-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.46 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.42 (d, J=8.1Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.19 (dd, J=8.1, 1.5 Hz, 1H), 7.11 (d,J=8.1 Hz, 2H), 6.92 (d, J=8.1 Hz, 2H), 6.65 (s, 1H), 5.35 (s, 2H), 4.40(s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.97-3.76 (m, 2H), 3.64-3.52 (m,2H), 3.46-3.35 (m, 2H), 2.56-2.38 (m, 2H), 2.35 (s, 3H), 2.28 (s, 3H),2.30-2.10 (m, 2H), 1.91-1.46 (m, 5H), 1.46-1.30 (m, 2H), 0.96 (t, J=6.9Hz, 3H), 0.95 (d, J=6.3 Hz, 6H).

EXAMPLE 37(2)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-dimethylaminophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.78 (d, J=8.7Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 4.40 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz,1H), 3.82 (m, 2H), 3.42 (m, 4H), 3.26 (s, 6H), 2.56 (m, 2H), 2.18 (m,2H), 1.88-1.30 (m, 7H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H),0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 37(3)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-diethylaminophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.96-7.82 (m,2H), 7.74-7.55 (m, 2H), 4.40 (s, 2H), 4.00 (dd, J=7.5, 4.5 Hz, 1H),3.93-3.60 (m, 6H), 3.55-3.40 (m, 4H), 2.65-2.48 (m, 2H), 2.25-2.06 (m,2H), 1.89-1.26 (m, 7H), 1.15 (t, J=7.2 Hz, 6H), 1.00-0.87 (m, 9H).

EXAMPLE 37(4)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-cyclohexyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.45-7.42 (m,2H), 7.02-6.99 (m, 2H), 4.40-4.31 (m, 1H), 4.27 (s, 2H), 4.00 (dd,J=8.0, 4.5 Hz, 1H), 3.83-3.70 (m, 2H), 3.47 (brd, 2H), 3.42-3.35 (m,2H), 2.43-2.32 (m, 2H), 2.24-2.11 (m, 2H), 2.00-1.93 (m, 2H), 1.86-1.32(m, 15H), 0.97-0.92 (m, 9H).

EXAMPLE 37(5)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.70 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52-7.47 (m,2H), 7.22-7.19 (m, 2H), 7.04-7.00 (m, 2H), 6.94-6.90 (m, 2H), 4.32 (s,2H), 4.01 (dd, J=8.0, 4.5 Hz, 1H), 3.86-3.73 (m, 2H), 3.48 (brd, 2H),3.42-3.34 (m, 2H), 2.45-2.33 (m, 5H), 2.25-2.12 (m, 2H), 1.85-1.48 (m,5H), 1.41-1.31 (m, 2H), 0.97-0.92 (m, 9H).

EXAMPLE 37(6)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.65 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.49-7.46 (m,2H), 7.00-6.94 (m, 6H), 4.31 (s, 2H), 4.01 (dd, J=8.0, 4.5 Hz, 1H),3.84-3.71 (m, 5H), 3.48 (brd, 2H), 3.40-3.31 (m, 2H), 2.42-2.30 (m, 2H),2.25-2.12 (m, 2H), 1.83-1.48 (m, 5H), 1.41-1.30 (m, 2H), 0.97-0.92 (m,9H).

EXAMPLE 37(7)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-butylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.46 (d, J=8.1Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 4.31 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz,1H), 3.84-3.68 (m, 2H), 3.54-3.36 (m, 4H), 2.67 (t, J=7.8 Hz, 2H),2.48-2.30 (m, 2H), 2.26-2.08 (m, 2H), 1.90-1.28 (m, 11H), 0.96 (t, J=7.2Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.94 (t, J=7.2Hz, 3H).

EXAMPLE 37(8)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(2-methylpropyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=6.9Hz, 2H), 7.30 (d, J=6.9 Hz, 2H), 4.33 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz,1H), 3.90-3.70 (m, 2H), 3.56-3.34 (m, 4H), 2.53 (d, J=7.2 Hz, 2H),2.53-2.30 (m, 2H), 2.24-2.08 (m, 2H), 1.96-1.26 (m, 8H), 0.95 (t, J=7.8Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6Hz, 6H).

EXAMPLE 37(9)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-fluorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.4Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.16-7.04 (m, 4H), 4.33 (s, 2H), 4.02(dd, J=7.8, 4.8 Hz, 1H), 3.88-3.68 (m, 2H), 3.58-3.36 (m, 4H), 2.46-2.10(m, 4H), 1.90-1.24 (m, 7H), 0.96 (t, J=6.9 Hz, 3H), 0.95 (d, J=6.6 Hz,3H), 0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 37(10)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-hydroxy-4-methoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.20 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.03-6.94 (m,3H), 4.23 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.89 (s, 3H), 3.84-3.68(m, 2H), 3.56-3.36 (m, 4H), 2.42-2.08 (m, 4H), 1.88-1.24 (m, 7H), 0.96(t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 37(11)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-fluorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (hexane:ethyl acetate=1:1); NMR (CD₃OD): δ 7.64-7.54 (m,2H), 7.37-7.27 (m, 2H), 4.45 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz, 1H),3.94-3.81 (m, 2H), 3.54 (m, 2H), 3.36 (m, 2H), 2.38 (m, 2H), 2.19 (m,2H), 1.82-1.49 (m, 5H), 1.35 (m, 2H), 0.95 (t, J=7.5 Hz, 3H), 0.94 (d,J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H).

EXAMPLE 37(12)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-fluorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (hexane:ethyl acetate=1:1); NMR (CD₃OD): δ 7.52 (dt, J=8.3,6.0 Hz, 1H), 7.41-7.37 (m, 2H), 7.26 (t, J=8.3 Hz, 1H), 4.39 (s, 2H),4.01 (dd, J=7.5, 4.5 Hz, 1H), 3.89-3.76 (m, 2H), 3.50-3.38 (m, 4H),2.48-2.38 (m, 2H), 2.25-2.12 (m, 2H), 1.84-1.75 (m, 1H), 1.72-1.46 (m,4H), 1.42-1.28 (m, 2H), 0.99-0.92 (m, 9H).

EXAMPLE 37(13)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-fluorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (hexane:ethyl acetate=1:1); NMR (CD₃OD): δ 7.60 (dd, J=8.7,5.4 Hz, 2H), 7.24 (t, J=8.7 Hz, 2H), 4.36 (s, 2H), 3.99 (dd, J=7.5, 4.5Hz, 1H), 3.78 (m, 2H), 3.49-3.35 (m, 4H), 2.44-2.13 (m, 4H), 1.84-1.46(m, 5H), 1.37 (m, 2H), 0.99-0.95 (m, 9H).

EXAMPLE 37(14)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-chlorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.62 (hexane:ethyl acetate=1:1); NMR (CD₃OD): δ 7.72 (d, J=7.0Hz, 1H), 7.60 (dd, J=8.0, 1.5 Hz, 1H), 7.56-7.45 (m, 2H), 4.55 (s, 2H),4.00 (dd, J=7.5, 4.5 Hz, 1H), 3.94 (m, 2H), 3.55 (r, 2H), 3.42-3.32 (m,2H), 2.43-2.37 (m, 2H), 2.26-2.13 (m, 2H), 1.85-1.46 (m, 5H), 1.35 (m,2H), 0.97-0.92 (m, 9H).

EXAMPLE 37(15)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-chlorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.55 (d, J=8.7Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 4.34 (s, 2H), 4.00 (dd, J=7.8, 4.5, Hz,1H), 3.88-3.68 (m, 2H), 3.51-3.34 (m, 4H), 2.49-2.52 (m, 2H), 2.26-2.08(m, 2H), 1.90-1.44 (m, 5H), 1.44-1.29 (m, 2H), 1.00-0.89 (m, 9H).

EXAMPLE 37(16)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-chlorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.68-7.64 (m,1H), 7.56-7.45 (m, 3H), 4.37 (s, 2H), 4.00 (dd, J=7.8, 4.5 Hz, 1H),3.91-3.72 (m, 2H), 3.54-3.32 (m, 4H), 2.53-2.34 (m, 2H), 2.27-2.08 (m,2H), 1.90-1.44 (m, 5H), 1.44-1.27 (m, 2H), 0.99-0.89 (m, 9H).

EXAMPLE 37(17)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-methyl-4-methoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.34 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.38-7.30 (m,2H), 6.99 (d, J=8.1 Hz, 1H), 4.25 (s, 2H), 4.00 (dd, J=7.8, 4.5 Hz, 1H),3.85 (s, 3H), 3.85-3.65 (m, 2H), 3.52-3.33 (m, 4H), 2.50-2.30 (m, 2H),2.22 (s, 3H), 2.20-2.07 (m, 2H), 1.90-1.43 (m, 5H), 1.43-1.28 (m, 2H),0.99-0.88 (m, 9H).

EXAMPLE 37(18)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(7-methoxy-1,3-benzodioxolan-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=20:1); NMR (CD₃OD): δ 6.85 (d, J=1.8Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 5.99 (s, 2H), 4.25 (s, 2H), 4.01 (dd,J=7.8, 4.5 Hz, 1H), 3.92 (s, 3H), 3.87-3.66 (m, 2H), 3.52-3.32 (m, 4H),2.52-2.34 (m, 2H), 2.26-2.08 (m, 2H), 1.90-1.43 (m, 5H), 1.43-1.29 (m,2H), 0.99-0.90 (m, 9H).

EXAMPLE 37(19)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenylthiophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.50-7.36 (m,7H), 7.30 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.00 (dd, J=7.8, 4.5 Hz, 1H),3.88-3.68 (m, 2H), 3.53-3.32 (m, 4H), 2.50-2.30 (m, 2H), 2.26-2.06 (m,2H), 1.90-1.42 (m, 5H), 1.42-1.27 (m, 2H), 0.98-0.89 (m, 9H).

EXAMPLE 37(20)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-methylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=19:1); NMR (CD₃OD): δ 7.57 (d, J=7.8Hz, 1H), 7.42-7.28 (m, 3H), 4.41 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H),3.89 (m, 2H), 3.53 (m, 2H), 3.42 (m, 2H), 2.48 (s, 3H), 2.48 (m, 2H),2.16 (m, 2H), 1.90-1.42 (m, 5H), 1.36 (sextet, J=7.2 Hz, 2H), 0.94 (d,J=6.6 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 37(21)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-methylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.31 (chloroform:methanol=19:1); NMR (CD₃OD): δ 7.41-7.29 (m,4H), 4.31 (s, 2H), 4.00 (dd, J=7.8, 4.8 Hz, 1H), 3.79 (m, 2H), 3.52-3.34(m, 4H), 2.40 (m, 2H), 2.40 (s, 3H), 2.17 (m, 2H), 1.90-1.44 (m, 5H),1.36 (sextet, J=7.5 Hz, 2H), 0.94 (t, J=7.5 Hz, 3H), 0.94 (d, J=6.6 Hz,3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 37(22)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.31 (chloroform:methanol=19:1); NMR (CD₃OD): δ 7.43 (d, J=7.8Hz, 2H), 7.31 (d, J=7.8 Hz, 2H), 4.31 (s, 2H), 4.00 (dd, J=7.8, 4.8 Hz,1H), 3.78 (m, 2H), 3.52-3.35 (m, 4H), 2.40 (m, 2H), 2.37 (s, 3H), 2.17(m, 2H), 1.88-1.44 (m, 5H), 1.36 (sextet, J=7.5 Hz, 2H), 0.94 (t, J=7.5Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 37(23)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(1-methylethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.48 (d, J=8.4Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz,1H), 3.88-3.70 (m, 2H), 3.54-3.36 (m, 4H), 3.04-2.88 (m, 1H), 2.48-2.30(m, 2H), 2.28-2.08 (m, 2H), 1.90-1.28 (m, 7H), 1.26 (d, J=6.9 Hz, 6H),0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H).

EXAMPLE 37(24)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-fluoro-4-methoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.32 (m,2H), 7.21 (m, 1H), 4.31 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz, 1H), 3.92 (s,3H), 3.86-3.64 (m, 2H), 3.58-3.36 (m, 4H), 2.56-2.32 (m, 2H), 2.28-2.08(m, 2H), 1.90-1.26 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.6 Hz,3H), 0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 37(25)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(2-hydroxyethyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.22 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.48 (d, J=8.7Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 4.29 (s, 2H), 4.09 (t, J=5.1 Hz, 2H),4.01 (dd, J=7.5, 4.5 Hz, 1H), 3.88 (t, J=5.1 Hz, 2H), 3.86-3.64 (m, 2H),3.54-3.36 (m, 4H), 2.50-2.30 (m, 2H), 2.26-2.08 (m, 2H), 1.90-1.24 (m,7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz,3H).

EXAMPLE 37(26)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-hydroxy-3-methylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.66 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.24 (d, J=7.7Hz, 2H), 6.89 (t, J=7.7 Hz, 1H), 4.36 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz,1H), 3.95-3.76 (m, 2H), 3.58-3.36 (m, 4H), 2.44-2.08 (m, 4H), 2.89 (s,3H), 1.90-1.24 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H),0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 37(27)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-trifluoromethyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.71 (d, J=7.8Hz, 2H), 7.42 (d, J=7.8 Hz, 2H), 4.41 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz,1H), 3.90-3.72 (m, 2H), 3.56-3.36 (m, 4H), 2.56-2.36 (m, 2H), 2.26-2.08(m, 2H), 1.90-1.28 (m, 7H), 0.95 (t, J=7.5 Hz, 3H), 0.95 (d, J=6.3 Hz,3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 37(28)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-methyl-5-chloro-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.59-7.50 (m,5H), 4.35 (s, 2H), 4.03 (dd, J=7.8, 4.5 Hz, 1H), 3.98-3.80 (m, 2H),3.72-3.58 (m, 2H), 3.46-3.38 (m, 2H), 2.58-2.38 (m, 2H), 2.45 (s, 3H),2.36-2.18 (m, 2H), 1.92-1.24 (m, 7H), 0.97 (t, J=7.5 Hz, 3H), 0.96 (d,J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 37(29)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(6-phenylpyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD): δ 9.17 (s, 1H),8.80 (m, 1H), 8.39 (m, 1H), 8.03-7.97 (m, 2H), 7.73-7.65 (m, 3H), 4.65(s, 2H), 4.03 (dd, J=7.2, 4.2 Hz, 1H), 4.02-3.82 (m, 2H), 3.64-3.42 (m,2H), 3.78-3.56 (m, 2H), 2.30-2.08 (m, 2H), 1.88-1.24 (m, 7H), 0.96 (d,J=6.3 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 37(30)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.18 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54 (d, J=8.7Hz, 2H), 7.30 (d, J=9.0 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.04 (d, J=9.0Hz, 2H), 4.34 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.88-3.68 (m, 2H),3.56-3.35 (m, 4H), 2.96 (s, 3H), 2.50-2.08 (m, 4H), 1.88-1.26 (m, 7H),0.96 (t, J=6.9 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 37(31)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylsulfonylaminophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.15 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.49 (d, J=8.7Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 4.33 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz,1H), 3.96-3.76 (m, 2H), 3.66-3.58 (m, 2H), 3.56-3.42 (m, 2H), 3.05 (s,3H), 2.68-2.46 (m, 2H), 2.44 (s, 3H), 2.41 (s, 3H), 2.32-2.10 (m, 2H),1.90-1.28 (m, 7H), 0.97 (t, J=6.6 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H), 0.95(d, J=6.3 Hz, 3H).

EXAMPLE 37(32)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(5-methylpyridin-2-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.29 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.12 (s, 1H),7.93 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H),7.06 (d, J=8.4 Hz, 1H), 4.40 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz, 1H),3.94-3.76 (m, 2H), 3.58-3.40 (m, 4H), 2.56-2.36 (m, 2H), 2.38 (s, 3H),2.30-2.08 (m, 2H), 1.88-1.24 (m, 7H), 0.96 (t, J=7.8 Hz, 3H), 0.96 (d,J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 37(33)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(6-methylpyridin-1-oxido-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.24 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.47 (s, 1H),7.71 (d, J=8.7 Hz, 2H), 7.62-7.48 (m, 2H), 7.29 (d, J=8.7 Hz, 2H), 4.40(s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.92-3.72 (m, 2H), 3.58-3.38 (m,4H), 2.64-2.40 (m, 2H), 2.60 (s, 3H), 2.28-2.10 (m, 2H), 1.90-1.28 (m,7H), 0.96 (t, J=7.8 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz,3H).

EXAMPLE 37(34)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(1-(2-methylpropyloxycarbonyl)indol-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.23 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.16 (d, J=8.4Hz, 1H), 7.82 (d, J=1.5 Hz, 1H), 7.78 (d, J=3.6 Hz, 1H), 7.50 (dd,J=8.4, 1.5 Hz, 1H), 6.75 (d, J=3.6 Hz, 1H), 4.46 (s, 2H), 4.27 (d, J=6.6Hz, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.82-3.74 (m, 2H), 3.58-3.36 (m,4H), 2.48-2.30 (m, 2H), 2.26-2.08 (m, 3H), 1.88-1.24 (m, 7H), 1.09 (s,3H), 1.06 (s, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94(d, J=6.3 Hz, 3H).

EXAMPLE 37(35)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-phenyl-5-methyloxazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.32 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.05-8.02 (m,2H), 7.52-7.50 (m, 3H), 4.35 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H),3.98-3.80 (m, 2H), 3.70-3.58 (m, 2H), 3.44-3.38 (m, 2H), 2.53 (s, 3H),2.53-2.36 (m, 2H), 2.34-2.14 (m, 2H), 1.90-1.26 (m, 7H), 0.96 (t, J=7.2Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 37(36)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.4Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 4.64 (m, 1H), 4.29 (s, 2H), 4.01 (dd,J=7.5, 4.5 Hz, 1H), 3.98-3.91 (m, 2H), 3.84-3.68 (m, 2H), 3.64-3.56 (m,2H), 3.50-3.37 (m, 4H), 2.50-2.30 (m, 2H), 2.24-1.98 (m, 4H), 1.88-1.26(m, 9H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3Hz, 3H).

EXAMPLE 37(37)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.22 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.55 (d, J=2.7Hz, 1H), 8.10 (dd, J=9.0, 2.7 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.72 (d,J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 4.40 (s, 2H), 4.02 (dd, J=7.8,4.5 Hz, 1H), 3.94-3.70 (m, 2H), 3.58-3.38 (m, 4H), 2.74 (s, 3H),2.60-2.42 (m, 2H), 2.28-2.08 (m, 2H), 1.90-1.26 (m, 7H), 0.96 (t, J=7.5Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 37(38)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-fluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.58 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.55-7.46 (m,2H), 7.36-7.25 (m, 2H), 4.30 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H),3.95-3.73 (m, 2H), 3.66-3.55 (m, 2H), 3.52-3.40 (m, 2H), 2.63-2.45 (m,2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.30-2.10 (m, 2H), 1.90-1.43 (m, 5H),1.43-1.30 (m, 2H), 0.99-0.91 (m, 9H).

EXAMPLE 37(39)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(pyridin-2-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.52 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.55 (d, J=4.8Hz, 1H), 8.12 (dd, J=8.4, 7.2 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.50 (dd,J=7.2, 4.8 Hz, 1H), 4.32 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H),3.96-3.73 (m, 2H), 3.67-3.55 (m, 2H), 3.54-3.40 (m, 2H), 2.69 (s, 3H),2.70-2.48 (m, 2H), 2.44 (s, 3H), 2.28-2.08 (m, 2H), 1.92-1.43 (m, 5H),1.43-1.26 (m, 2H), 0.99-0.90 (m, 9H).

EXAMPLE 37(40)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.30 (d, J=9.0Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.33 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz,1H), 3.92-3.77 (m, 2H), 3.61 (m, 2H), 3.47 (m, 2H), 2.58 (m, 2H), 2.45(s, 3H), 2.36 (s, 3H), 2.20 (m, 2H), 1.88-1.76 (m, 1H), 1.73-1.32 (m,6H), 0.96 (t, J=7.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz,3H).

EXAMPLE 37(41)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(2-carboxyethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.0Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 4.31 (s, 2H), 4.00 (dd, J=7.5, 4.5 Hz,1H), 3.86-3.73 (m, 2H), 3.49-3.35 (m, 4H), 2.96 (t, J=7.5 Hz, 2H), 2.62(t, J=7.5 Hz, 2H), 2.44-2.33 (m, 2H), 2.23-2.11 (m, 2H), 1.84-1.32 (m,7H), 0.94 (t, J=7.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz,3H).

EXAMPLE 37(42)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(dimethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.54 (chloroform:methanol=9:1); NMR (CD₃OD): δ 7.96 (d, J=8.7Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.02 (dd, J=7.8, 4.8 Hz,1H), 3.95-3.75 (m, 2H), 3.66-3.56 (m, 2H), 3.47 (m, 2H), 2.74 (s, 6H),2.56 (m, 2H), 2.48 (s, 3H), 2.41 (s, 3H), 2.30-2.12 (m, 2H), 1.90-1.46(m, 5H), 1.38 (sextet, J=7.2 Hz, 2H), 0.98-0.93 (m, 9H).

EXAMPLE 37(43)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(5-methylpyridin-1-oxido-2-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=9:1); NMR (CD₃OD): δ 7.77 (brs, 1H),7.65-7.59 (m, 2H), 7.56 (dd, J=9.3, 2.4 Hz, 1H), 7.03-6.97 (m, 2H), 6.73(d, J=9.3 Hz, 1H), 4.33 (s, 2H), 4.00 (dd, J=7.8, 4.8 Hz, 1H), 3.86-3.68(m, 2H), 3.51-3.36 (m, 4H), 2.46 (m, 2H), 2.25-2.07 (m, 2H), 2.18 (s,3H), 1.90-1.44 (m, 5H), 1.36 (sextet, J=7.2 Hz, 2H), 0.97-0.91 (m, 9H).

EXAMPLE 37(44)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(2-carboxy-1-ethenyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.20 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.75 (d, J=8.4Hz, 2H), 7.70 (d, J=16.2 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 6.58 (d,J=16.2 Hz, 2H), 4.39 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.92-3.74(m, 2H), 3.58-3.36 (m, 4H), 2.50-2.32 (m, 2H), 2.30-2.10 (m, 2H),1.90-1.24 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94(d, J=6.3 Hz, 3H).

EXAMPLE 37(45)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(2-carboxy-1-ethenyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.69-7.57 (m,5H), 7.14 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 6.42 (d, J=15.9 Hz,1H), 4.36 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.92-3.70 (m, 2H),3.56-3.35 (m, 4H), 2.48-2.30 (m, 2H), 2.30-2.12 (m, 2H), 1.88-1.25 (m,7H), 0.98-0.88 (m, 9H).

EXAMPLE 37(46)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-aminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.90 (d, J=8.7Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.36 (s, 2H), 4.01 (dd, J=7.8, 4.5, Hz, 1H), 3.90-3.70 (m, 2H),3.58-3.35 (m, 4H), 2.54-2.36 (m, 2H), 2.30-2.10 (m, 2H), 1.90-1.26 (m,7H), 1.00-0.86 (m, 9H).

EXAMPLE 37(47)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-aminosulfonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD): 7.90 (d, J=8.7 Hz,2H), 7.57 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.7 Hz,2H), 4.28 (brs, 2H), 4.01 (dd, J=7.8, 4.5, Hz, 1H), 3.83-3.60 (m, 2H),3.49-3.34 (m, 4H), 2.44-2.26 (m, 2H), 2.26-2.09 (m, 2H), 1.89-1.26 (m,7H), 1.00-0.88 (m, 9H).

EXAMPLE 37(48)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-benzylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.41-7.33 (m,3H), 7.21-7.19 (m, 2H), 5.45 (s, 2H), 4.30 (s, 2H), 4.01 (dd, J=7.5, 4.5Hz, 1H), 3.89-3.73 (m, 2H), 3.60-3.46 (m, 4H), 2.61 (m, 2H), 2.48 (s,3H), 2.46 (s, 3H), 2.23-2.11 (m, 2H), 1.87-1.31 (m, 7H), 0.95 (t, J=7.0Hz, 3H), 0.94 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H).

EXAMPLE 37(49)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(2,4-difluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.53 (m,1H), 7.33-7.26 (m, 1H), 7.23-7.16 (m, 1H), 4.31 (s, 2H), 4.02 (dd,J=7.5, 4.5 Hz, 1H), 3.92-3.76 (m, 2H), 3.63-3.56 (m, 2H), 3.49-3.45 (m,2H), 2.57 (m, 2H), 2.40 (s, 3H), 2.29 (s, 3H), 2.19 (m, 2H), 1.86-1.34(m, 7H), 0.96 (t, J=7.0 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5Hz, 3H).

EXAMPLE 37(50)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyrrolidin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.10 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.75 (d, J=8.4Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 4.43 (s, 2H), 4.40 (s, 2H), 4.00 (dd,J=7.5, 4.5 Hz, 1H), 3.92-3.70 (m, 2H), 3.56-3.40 (m, 6H), 3.25-3.12 (m,2H), 2.68-2.48 (m, 2H), 2.28-1.95 (m, 6H), 1.88-1.42 (m, 5H), 1.42-1.30(m, 2H), 0.98-0.90 (m, 9H).

EXAMPLE 37(51)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholin-4-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.43 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.95 (d, J=8.7Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.02 (dd, J=7.8, 4.8 Hz,1H), 3.95-3.72 (m, 2H), 3.76-3.67 (m, 4H), 3.66-3.57 (m, 2H), 3.56-3.42(m, 2H), 3.08-2.95 (m, 4H), 2.70-2.50 (m, 2H), 2.50 (s, 3H), 2.42 (s,3H), 2.31-2.10 (m, 2H), 1.90-1.44 (m, 5H), 1.44-1.30 (m, 2H), 1.00-0.91(m, 9H).

EXAMPLE 37(52)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(methylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.21 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.01 (d, J=8.4Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 4.34 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz,1H), 3.98-3.78 (m, 2H), 3.66-3.58 (m, 2H), 3.44-3.30 (m, 2H), 2.59 (s,3H), 2.54-2.38 (m, 2H), 2.47 (s, 3H), 2.40 (s, 3H), 2.36-2.16 (m, 2H),1.90-1.26 (m, 7H), 0.97 (t, J=7.5 Hz, 3H), 0.96 (d, J=6.6 Hz, 6H).

EXAMPLE 37(53)(3S)-1-butyl-25-dioxo-3-(2-methylpropyl)-9-(4-(4-cyanophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.30 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.75 (d, J=8.4Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.7Hz, 2H), 4.39 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.94-3.72 (m, 2H),3.58-3.36 (m, 4H), 2.58-2.38 (m, 2H), 2.28-2.08 (m, 2H), 1.88-1.24 (m,7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz,3H).

EXAMPLE 37(54)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(dimethylaminomethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.16 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.76 (d, J=8.1Hz, 2H), 7.63 (d, J=8.1 Hz, 2H), 4.41 (s, 2H), 4.37 (s, 2H), 4.00 (dd,J=7.8, 4.8 Hz, 1H), 3.90-3.72 (m, 2H), 3.50-3.42 (m, 4H), 2.87 (s, 6H),2.65-2.50 (m, 2H), 2.22-2.04 (m, 2H), 1.88-1.32 (m, 7H), 0.97-0.92 (m,9H).

EXAMPLE 37(55)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-dimethylaminoethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.13 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.07 (d, J=8.7Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.01 (dd, J=8.1, 5.1 Hz,1H), 3.95-3.74 (m, 2H), 3.68-3.45 (m, 4H), 3.40-3.20 (m, 4H,), 2.95 (s,6H), 2.70-2.50 (m, 2H), 2.49 (s, 3H), 2.41 (s, 3H), 2.28-2.12 (m, 2H),1.88-1.34 (m, 7H), 0.98-0.92 (m, 9H).

EXAMPLE 37(56)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(4-hydroxyphenyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.81 (s, 1H),7.69 (d, J=7.5 Hz, 1H), 7.53 (d, J=9.0 Hz, 2H), 7.55-7.48 (m, 1H), 7.45(d, J=7.5 Hz, 1H), 6.87 (d, J=9.0 Hz, 2H), 4.40 (s, 2H), 4.00 (dd,J=7.5, 4.5 Hz, 1H), 3.94-3.73 (m, 2H), 3.56-3.44 (m, 2H), 3.44-3.30 (m,2H), 2.53-2.33 (m, 2H), 2.26-2.08 (m, 2H), 1.90-1.40 (m, 5H), 1.43-1.25(m, 2H), 0.94 (d, J=6.3 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.3Hz, 3H).

EXAMPLE 37(57)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(3-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.5Hz, 2H), 7.28 (t, J=8.3 Hz, 1H), 7.07 (d, J=8.5 Hz, 2H), 6.75 (ddd,J=8.3, 2.3, 1.0 Hz, 1H), 6.60-6.57 (m, 2H), 4.33 (s, 2H), 4.01 (dd,J=7.5, 4.5 Hz, 1H), 3.86-3.73 (m, 2H), 3.77 (s, 3H), 3.51-3.34 (m, 4H),2.41 (m, 2H), 2.42-2.12 (m, 2H), 1.84-1.33 (m, 7H), 0.95 (t, J=7.2 Hz,3H), 0.94 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H).

EXAMPLE 37(58)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(quinoxalin-2-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.52 (chloroform:methanol=10:1); NMR (CD₃OD): δ 9.51 (s, 1H),8.12 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.90-7.80 (m, 2H), 4.37(s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.96-3.81 (m, 2H), 3.63 (m, 2H),3.44 (m, 2H), 2.92 (s, 3H), 2.47 (s, 3H), 2.47 (m, 2H), 2.29-2.17 (m,2H), 1.86-1.33 (m, 7H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H),0.94 (d, J=6.5 Hz, 3H).

EXAMPLE 37(59)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenylcarbonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.76 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.88 (d, J=8.4Hz, 2H), 7.81-7.67 (m, 5H), 7.57-7.52 (m, 2H), 4.49 (s, 2H), 4.01 (dd,J=8.1, 4.8 Hz, 1H), 4.00-3.78 (m, 2H), 3.59-3.48 (m, 2H), 3.44-3.35 (m,2H), 2.50-2.32 (m, 2H), 2.32-2.14 (m, 2H), 1.88-1.24 (m, 7H), 1.02-0.88(m, 9H).

EXAMPLE 37(60)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-(2-hydroxyethyl)-N-methylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.00 (d, J=8.7Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 4.34 (s, 2H), 4.04 (dd, J=7.8, 4.5 Hz,1H), 3.98-3.76 (m, 2H), 3.70 (t, J=5.7 Hz, 2H), 3.68-3.58 (m, 2H),3.50-3.38 (m, 2H), 3.20 (t, J=5.7 Hz, 2H), 2.88 (s, 3H), 2.58-2.38 (m,2H), 2.48 (s, 3H), 2.41 (s, 3H), 2.36-2.16 (m, 2H), 1.90-1.24 (m, 7H),0.97 (t, J=6.9 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 37(61)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(2-phenylethyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.24 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.31-7.23 (m,3H), 7.10 (d, J=6.6 Hz, 2H), 4.44 (t, J=6.3 Hz, 2H), 4.21 (s, 2H), 4.03(dd, J=7.8, 4.8 Hz, 1H), 3.82-3.60 (m, 2H), 3.58-3.32 (m, 4H), 3.13 (t,J=6.3 Hz, 2H), 2.72-2.52 (m, 2H), 2.50 (s, 3H), 2.24-2.04 (m, 2H), 1.99(s, 3H), 1.90-1.36 (m, 7H), 0.97 (t, J=7.2 Hz, 3H), 0.96 (d, J=6.6 Hz,3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 37(62)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(1,3,5-trimethylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 4.28 (s, 2H),4.00 (dd, J=7.8, 4.8 Hz, 1H), 3.87 (s, 3H), 3.87-3.69 (m, 2H), 3.60-3.43(m, 4H), 2.69-2.50 (m, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.26-2.08 (m,2H), 1.90-1.28 (m, 7H), 0.98-0.85 (m, 9H).

EXAMPLE 37(63)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(morpholin-4-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.56 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.74 (d, J=8.4Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 4.40 (s, 4H), 4.00 (dd, J=7.5, 4.5 Hz,1H), 4.10-3.70 (m, 6H), 3.54-3.42 (m, 4H), 3.40-3.16 (m, 4H), 2.65-2.46(m, 2H), 2.24-2.03 (m, 2H), 1.88-1.28 (m, 7H), 1.02-0.88 (m, 9H).

EXAMPLE 37(64)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylpiperazin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.64 (chloroform:methanol=5:1); NMR (CD₃OD): δ 7.45 (m, 4H),4.55 (s, 2H), 4.42 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz, 1H), 3.88-3.56 (m,10H), 3.53-3.43 (m, 4H), 3.01 (s, 3H), 2.59-2.47 (m, 2H), 2.22-2.09 (m,2H), 1.85-1.33 (m, 7H), 0.94 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H),0.93 (d, J=6.5 Hz, 3H).

EXAMPLE 37(65)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-phenylsulfonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.70 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 8.08 (d, J=8.4Hz, 2H), 8.02-7.96 (m, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.70-7.55 (m, 3H),4.43 (s, 2H), 3.99 (dd, J=7.8, 4.8 Hz, 1H), 3.91-3.72 (m, 2H), 3.48-3.34(m, 4H), 2.48-2.32 (m, 2H), 2.23-2.06 (m, 2H), 1.88-1.43 (m, 5H), 1.34(sextet, J=7.2 Hz, 2H), 0.96-0.90 (m, 9H).

EXAMPLE 37(66)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.28 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 4.35-4.20 (m,3H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.90-3.68 (m, 2H), 3.58-3.41 (m, 4H),2.60-2.46 (m, 2H), 2.45 (s, 3H), 2.40 (s, 3H), 2.26-2.08 (m, 2H),1.98-1.26 (m, 17H), 0.98-0.91 (m, 9H).

EXAMPLE 37(67)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(3-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.11 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 7.83 (ddd,J=7.8, 1.5, 0.9 Hz, 1H), 7.61 (dd, J=2.4, 1.5 Hz, 1H), 7.58 (d, J=8.7Hz, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.29 (ddd, J=7.8, 2.4, 0.9 Hz, 1H),7.11 (d, J=8.7 Hz, 2H), 4.35 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H),3.90-3.72 (m, 2H), 3.57-3.36 (m, 4H), 2.50-2.34 (m, 2H), 2.28-2.09 (m,2H), 1.89-1.44 (m, 5H), 1.36 (sextet, J=7.2 Hz, 2H), 0.98-0.91 (m, 9H).

EXAMPLE 37(68)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(piperidin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.52 (chloroform:methanol=9:1); NMR (CD₃OD): δ 7.75 (d, J=8.4Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 4.41 (s, 2H), 4.34 (s, 2H), 4.00 (dd,J=7.8, 4.5 Hz, 1H), 3.91-3.71 (m, 2H), 3.54-3.41 (m, 6H), 3.05-2.91 (m,2H), 2.67-2.49 (m, 2H), 2.25-2.05 (m, 2H), 2.00-1.28 (m, 13H), 0.98-0.91(m, 9H).

EXAMPLE 37(69)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.36 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 8.01 (d, J=8.7Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.02 (dd, J=7.8, 4.8 Hz,1H), 3.95-3.74 (m, 2H), 3.66-3.55 (m, 2H), 3.50-3.40 (m, 2H), 3.34-3.24(m, 4H), 2.62-2.47 (m, 2H), 2.48 (s, 3H), 2.40 (s, 3H), 2.30-2.11 (m,2H), 1.90-1.45 (m, 9H), 1.38 (sextet, J=7.2 Hz, 2H), 1.00-0.90 (m, 9H).

EXAMPLE 37(70)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2,3-dihydrobenzofuran-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.56 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 7.40 (brs,1H), 7.26 (dd, J=8.1, 1.8 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 4.59 (t,J=8.7 Hz, 2H), 4.26 (s, 2H), 4.00 (dd, J=7.8, 4.8 Hz, 1H), 3.84-3.66 (m,2H), 3.52-3.36 (m, 4H), 3.24 (t, J=8.7 Hz, 2H), 2.49-2.35 (m, 2H),2.25-2.08 (m, 2H), 1.89-1.43 (m, 5H), 1.36 (sextet, J=7.2 Hz, 2H),0.98-0.91 (m, 9H).

EXAMPLE 37(71)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.03 (d, J=8.7Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz,1H), 3.95-3.73 (m, 2H), 3.67-3.57 (m, 2H), 3.56 (t, J=5.7 Hz, 2H),3.51-3.40 (m, 2H), 3.01 (t, J=5.7 Hz, 2H), 2.63-2.42 (m, 2H), 2.47 (s,3H), 2.41 (s, 3H), 2.32-2.12 (m, 2H), 1.92-1.44 (m, 5H), 1.44-1.30 (m,2H), 1.00-0.91 (m, 9H).

EXAMPLE 37(72)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(carboxymethyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.30 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.7Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 4.71 (s, 2H), 4.29 (s, 2H), 4.00 (dd,J=7.8, 4.5 Hz, 1H), 3.88-3.67 (m, 2H), 3.53-3.33 (m, 4H), 2.46-2.28 (m,2H), 2.26-2.08 (m, 2H), 1.90-1.27 (m, 7H), 0.99-0.90 (m, 9H).

EXAMPLE 37(73)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(1-phenyl-1-hydroxymethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.23 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.62-7.18 (m,9H), 5.82 (s, 1H), 4.33 (s, 2H), 4.00 (dd, J=7.8, 4.8 Hz, 1H), 3.88-3.68(m, 2H), 3.56-3.36 (m, 4H), 2.48-2.28 (m, 2H), 2.24-2.06 (m, 2H),1.88-1.24 (m, 7H), 0.95 (t, J=6.6 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.93(d, J=6.3 Hz, 3H).

EXAMPLE 37(74)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-hydroxypiperidin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.16 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.73 (d, J=7.8Hz, 2H), 7.69-7.61 (m, 2H), 4.42 (s, 2H), 4.40-4.34 (m, 2H), 4.11-4.05(m, 1H), 4.00 (dd, J=7.5, 4.5 Hz, 1H), 3.93-3.72 (m, 2H), 3.55-3.38 (m,4H), 3.16-3.00 (m, 1H), 2.60-2.38 (m, 2H), 2.26-2.06(m, 3H), 2.00-1.88(m, 2H), 1.88-1.43 (m, 9H), 1.43-1.14 (m, 2H), 0.98-0.90 (m, 9H).

EXAMPLE 37(75)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(3-carboxyphenylmethyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.58 (chloroform:methanol=5:1); NMR (CD₃OD): δ 8.10 (s, 1H),7.98 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H),7.47 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H), 5.22 (s, 2H), 4.29 (s,2H), 4.01 (dd, J=7.5, 4.5 Hz, 1H), 3.86-3.68 (m, 2H), 3.54-3.32 (m, 4H),2.42-2.08 (m, 4H), 1.90-1.28 (m, 7H), 0.95 (t, J=6.9 Hz, 3H), 0.95 (d,J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 37(76)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(bis(methylsulfonyl)amino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.64 (chloroform:methanol=5:1); NMR (CD₃OD): δ 7.72 (d, J=8.4Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 4.44 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.96-3.78 (m, 2H), 3.58-3.36 (m, 4H), 3.47 (s, 6H), 2.50-2.12 (m,4H), 1.92-1.28 (m, 7H), 0.96 (t, J=6.9 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H),0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 37(77)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(1,4-benzodioxan-6-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.49 (d, J=8.7Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.85 (m, 1H), 6.55-6.51 (m, 2H), 4.33(s, 2H), 4.24 (s, 4H), 4.02 (dd, J=7.5, 4.8 Hz, 1H), 3.88-3.70 (m, 2H),3.56-3.32 (m, 4H), 2.42-2.10 (m, 4H), 1.92-1.24 (m, 7H), 0.96 (t, J=7.2Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 37(78)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(3-hydroxyphenyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.19 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.83 (s, 1H),7.74 (m, 1H), 7.59-7.51 (m, 2H), 7.28 (m, 1H), 7.16-7.09 (m, 2H), 6.81(m, 1H), 4.44 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.94-3.76 (m, 2H),3.58-3.32 (m, 4H), 2.50-2.32 (m, 2H), 2.28-2.08 (m, 2H), 1.88-1.26 (m,7H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz,3H).

EXAMPLE 37(79)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(methylsulfonylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=8.4Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz,1H), 3.88-3.72 (m, 2H), 3.52-3.14 (m, 4H), 3.01 (s, 3H), 2.46-2.30 (m,2H), 2.28-2.10 (m, 2H), 1.88-1.10 (m, 7H), 0.98-0.90 (m, 9H).

EXAMPLE 37(80)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(6-(4-methoxyphenyloxy)pyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.30 (m, 1H),8.05 (m, 1H), 7.10-6.86 (m, 5H), 4.39 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz,1H), 3.90-3.74 (m, 2H), 3.81 (s, 3H), 3.54-3.32 (m, 4H), 2.54-2.32 (m,2H), 2.28-2.05 (m, 2H), 1.88-1.26 (m, 7H), 0.98-0.90 (m, 9H).

EXAMPLE 37(81)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.39 (brd, J=4.5Hz, 1H), 7.84 (d, J=9.0 Hz, 2H), 7.59 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.35 (s, 2H), 4.01 (m, 1H), 3.86-3.73(m, 2H), 3.53-3.41 (m, 4H), 2.91 (d, J=4.5 Hz, 3H), 2.55-2.30 (m, 2H),2.30-2.10 (m, 2H), 1.90-1.30 (m, 7H), 0.95 (t, J=6.9 Hz, 3H), 0.94 (d,J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 37(82)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-chlorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.4Hz, 2H), 7.38 (d, J=9.0 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.0Hz, 2H), 4.31 (s, 2H), 4.01 (m, 1H), 3.90-3.70 (m, 2H), 3.60-3.30 (m,4H), 2.50-2.10 (m, 4H), 1.90-1.30 (m, 7H), 0.95 (t, J=7.2 Hz, 3H), 0.94(d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 37(83)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(4-carboxyphenyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=5:1); NMR (CD₃OD): δ 8.13 (d, J=9.0Hz, 2H), 7.93 (s, 1H), 7.84 (m, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.66-7.56(m, 2H), 4.46 (s, 2H), 4.02 (dd, J=7.5, 4.8 Hz, 1H), 3.96-3.74 (m, 2H),3.58-3.36 (m, 4H), 2.48-2.08 (m, 4H), 1.88-1.24 (m, 7H), 0.95 (t, J=6.9Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 37(84)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(phenylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.27 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.07 (d, J=8.4Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.72-7.67 (m, 2H), 7.38 (t, J=7.5 Hz,2H), 7.17 (t, J=7.5 Hz, 1H), 4.47 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H),3.96-3.76 (m, 2H), 3.58-3.36 (m, 4H), 2.54-2.36 (m, 2H), 2.28-2.12 (m,2H), 1.90-1.24 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H),0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 37(85)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylthiophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7Hz, 2H), 4.34 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.88-3.68 (m, 2H),3.56-3.36 (m, 4H), 2.48 (s, 3H), 2.48-2.32 (m, 2H), 2.28-2.08 (m, 2H),1.90-1.28 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94(d, J=6.3 Hz, 3H).

EXAMPLE 37(86)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(2-dimethylaminoethylaminocarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.11 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.93 (d, J=9.0Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.10 (d, J=9.0Hz, 2H), 4.36 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.88-3.70 (m, 4H),3.54-3.36 (m, 6H), 2.98 (s, 6H), 2.62-2.44 (m, 2H), 2.24-2.08 (m, 2H),1.88-1.30 (m, 7H), 0.98-0.90 (m, 9H).

EXAMPLE 37(87)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-aminocarbonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.17 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.98 (d, J=8.7Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 4.43 (s, 2H), 4.00 (dd, J=7.5, 4.5 Hz,1H), 3.92-3.74 (m, 2H), 3.52-3.36 (m, 4H), 2.58-2.40 (m, 2H), 2.26-2.08(m, 2H), 1.88-1.28 (m, 7H), 0.98-0.88 (m, 9H).

EXAMPLE 37(88)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-dimethylaminocarbonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.31 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.68 (d, J=8.1Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 4.41 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz,1H), 3.92-3.82 (m, 2H), 3.54-3.36 (m, 4H), 3.11 (s, 3H), 2.99 (s, 3H),2.56-2.38 (m, 2H), 2.26-2.08 (m, 2H), 1.86-1.28 (m, 7H), 1.00-0.86 (m,9H).

EXAMPLE 38(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 35 usingN-(t-butyloxycarbonyl)-L-cyclohexylalanine instead ofN-(t-butyloxycarbonyl-L-leucine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.35 (hexane:ethyl acetate=1:1); NMR (CDCl₃): δ 7.39-7.31 (m,5H), 6.48 (brs, 1H), 5.16 (s, 2H), 4.15 (brs, 2H), 4.00 (ddd, J=9.6,4.8, 1.5 Hz, 1H), 3.76-3.16 (m, 4H), 2.02-1.12 (m, 19H), 1.08-0.88 (m,2H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 39(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 9 using the compoundprepared in Example 38, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.08 (chloroform:methanol:acetic acid=90:10:1); NMR (CD₃OD): δ4.05 (dd, J=7.8, 4.8 Hz, 1H), 3.84-3.68 (m, 2H), 3.46-3.34 (m, 4H),2.40-2.04 (m, 4H), 1.83-1.46 (m, 10H), 1.39 (sextet, J=7.5 Hz, 2H),1.33-1.15 (m, 3H), 1.05-0.86 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).

EXAMPLE 40(1) TO 40(90)

By the same procedure as described in Example 10 using the compoundprepared in Example 39 and the corresponding aldehyde derivatives, thefollowing compounds of the present invention were obtained.

EXAMPLE 40(1)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.71 (ethyl acetate); NMR (CD₃OD): δ 7.50 (d, J=8.7 Hz, 2H),7.19 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H),4.32 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.87-3.69 (m, 2H), 3.55-3.42(m, 2H), 3.42-3.34 (m, 2H), 2.49-2.30 (m, 2H), 2.33 (s, 3H), 2.30-2.08(m, 2H), 1.82-1.10 (m, 15H), 1.05-0.85 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 40(2)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.67 (ethyl acetate); NMR (CD₃OD): δ 7.49 (d, J=8.4 Hz, 2H),7.02-6.92 (m, 6H), 4.31 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.86-3.69(m, 2H), 3.79 (s, 3H), 3.54-3.30 (m, 4H), 2.50-2.30 (m, 2H), 2.28-2.06(m, 2H), 1.83-1.10 (m, 15H), 1.05-0.83 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 40(3)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-fluorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (hexane:ethyl acetate=1:1); NMR (CD₃OD): δ 7.70-7.53 (m,2H), 7.38-7.23 (m, 2H), 4.44 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H),3.95-3.77 (m, 2H), 3.60-3.45 (m, 2H), 3.45-3.30 (m, 2H), 2.53-2.34 (m,2H), 2.28-2.08 (m, 2H), 1.83-1.10 (m, 15H), 1.05-0.82 (m, 2H), 0.94 (t,J=7.2 Hz, 3H).

EXAMPLE 40(4)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-fluorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.40 (hexane:ethyl acetate=1:1); NMR (CD₃OD): δ 7.57-7.48 (m,1H), 7.44-7.37 (m, 2H), 7.30-7.21 (m, 1H), 4.38 (s, 2H), 4.03 (dd,J=7.8, 4.8 Hz, 1H), 3.90-3.72 (m, 2H), 3.55-3.33 (m, 4H), 2.56-2.37 (m,2H), 2.25-2.04 (m, 2H), 1.82-1.08 (m, 15H), 1.06-0.83 (m, 2H), 0.95 (t,J=7.2 Hz, 3H).

EXAMPLE 40(5)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-fluorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.27 (hexane:ethyl acetate=1:1); NMR (CD₃OD): δ 7.62 (dd, J=8.7,5.1 Hz, 2H), 7.23 (dd, J=8.7, 8.7 Hz, 2H), 4.36 (s, 2H), 4.03 (dd,J=7.8, 4.8 Hz, 1H), 3.88-3.71 (m, 2H), 3.53-3.33 (m, 4H), 2.53-2.35 (m,2H), 2.27-2.04 (m, 2H), 1.82-1.10 (m, 15H), 1.05-0.82 (m, 2H), 0.94 (t,J=7.2 Hz, 3H).

EXAMPLE 40(6)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-chlorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (hexane:ethyl acetate=1:1); NMR (CD₃OD): δ 7.65 (m, 1H),7.55-7.49 (m, 3H), 4.37 (s, 2H), 4.04 (dd, J=7.0, 4.5 Hz, 1H), 3.83 (m,2H), 3.54-3.47 (m, 2H), 3.41-3.35 (m, 2H), 2.38 (m, 2H), 2.18 (m, 2H),1.78-1.47 (m, 9H), 1.42-1.17 (m, 6H), 0.95 (t, J=7.5 Hz, 3H), 0.97-0.92(m, 2H).

EXAMPLE 40(7)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-cyclohexyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.41 (d, J=8.7Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 4.36 (m, 1H), 4.24 (s, 2H), 4.03 (dd,J=7.8, 4.5 Hz, 1H), 3.82-3.65 (m, 2H), 3.50-3.30 (m, 4H), 2.42-2.25 (m,2H), 2.25-2.06 (m, 2H), 2.02-1.92 (m, 2H), 1.84-1.14 (m, 23H), 1.04-0.89(m, 5H).

EXAMPLE 40(8)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methoxy-3-hydroxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.01 (d, J=7.8Hz, 1H), 6.99-6.93 (m, 2H), 4.22 (s, 2H), 4.03 (dd, J=7.5, 4.8 Hz, 1H),3.87 (s, 3H), 3.83-3.67 (m, 2H), 3.52-3.42 (m, 2H), 3.42-3.33 (m, 2H),2.44-2.27 (m, 2H), 2.26-2.07 (m, 2H), 1.83-1.12 (m, 15H), 1.04-0.89 (m,5H).

EXAMPLE 40(9)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-chlorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.77 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.69 (dd, J=7.5,2.1 Hz, 1H), 7.60 (dd, J=7.5, 2.1 Hz, 1H), 7.51 (dt, J=2.1, 7.5 Hz, 1H),7.47 (dt, J=2.1, 7.5 Hz, 1H), 4.52 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz,1H), 4.00-3.82 (m, 2H), 3.60-3.48 (m, 2H), 3.43-3.34 (m, 2H), 2.48-2.29(m, 2H), 2.28-2.07 (m, 2H), 1.83-1.44 (m, 10H), 1.43-1.12 (m, 5H),1.04-0.88 (m, 5H).

EXAMPLE 40(10)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-methylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.77 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.56 (d, J=7.2Hz, 1H), 7.41-7.30 (m, 3H), 4.41 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H),3.98-3.79 (m, 2H), 3.57-3.48 (m, 2H), 3.44-3.39 (m, 2H), 2.56-2.38 (m,2H), 2.48 (s, 3H), 2.26-2.06 (m, 2H), 1.82-1.15 (m, 15H), 1.02-0.84 (m,5H).

EXAMPLE 40(11)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-methylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.58 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.28 (m,4H), 4.31 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.84-3.70 (m, 2H),3.52-3.46 (m, 4H), 2.51-2.30 (m, 2H), 2.39 (s, 3H), 2.24-2.04 (m, 2H),1.80-1.12 (m, 15H), 1.02-0.84 (m, 5H).

EXAMPLE 40(12)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.44 (d, J=8.4Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.88-3.70 (m, 2H), 3.52-3.36 (m, 4H), 2.48-2.30 (m, 2H), 2.38 (s,3H), 2.30-2.08 (m, 2H), 1.81-1.10 (m, 15H), 1.04-0.82 (m, 5H).

EXAMPLE 40(13)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-phenylthiophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.74 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50-7.37 (m,7H), 7.29 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.03 (dd, J=7.5, 4.8 Hz, 1H),3.84-3.70 (m, 2H), 3.50-3.32 (m, 4H), 2.56-2.38 (m, 2H), 2.24-2.05 (m,2H), 1.81-1.06 (m, 15H), 1.02-0.84 (m, 5H).

EXAMPLE 40(14)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-(2-methylpropyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=19:1); NMR (CD₃OD): δ 7.47 (d, J=7.5Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 4.32 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz,1H), 3.80 (m, 2H), 3.56-3.36 (m, 4H), 2.52 (d, J=7.2 Hz, 2H), 2.45 (m,2H), 2.16 (m, 2H), 1.96-1.14 (m, 16H), 0.97-0.89 (m, 11H).

EXAMPLE 40(15)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-butylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.37 (chloroform:methanol=19:1); NMR (CD₃OD): δ 7.46 (d, J=8.4Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.03 (dd, J=7.2, 4.8 Hz,1H), 3.79 (m, 2H), 3.56-3.36 (m, 4H), 2.66 (t, J=7.5 Hz, 2H), 2.41 (m,2H), 2.16 (m, 2H), 1.82-1.20 (m, 19H), 1.00-0.89 (m, 2H), 0.94 (t, J=7.2Hz, 3H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 40(16)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-isopropylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.46 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz,1H), 3.88-3.74 (m, 2H), 3.52-3.43 (m, 2H), 3.43-3.32 (m, 2H), 3.02-2.90(m, 1H), 2.45-2.25 (m, 2H), 2.25-2.08 (m, 2H), 1.80-1.12 (m, 21H),1.04-0.88 (m, 5H).

EXAMPLE 40(17)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methoxy-3-fluorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.58 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.31 (m,2H), 7.22-7.17 (m, 1H), 4.30 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz, 1H), 3.90(s, 3H), 3.86-3.70 (m, 2H), 3.50-3.38 (m, 4H), 2.52-2.32 (m, 2H),2.26-2.05 (m, 2H), 1.80-1.15 (m, 15H), 1.01-0.88 (m, 5H).

EXAMPLE 40(18)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(2-hydroxyethoxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.7Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 4.29 (s, 2H), 4.08-4.00 (m, 3H),3.89-3.84 (m, 2H), 3.84-3.68 (m, 2H), 3.52-3.36 (m, 4H), 2.48-2.30 (m,2H), 2.25-2.08 (m, 2H), 1.80-1.10 (m, 15H), 1.04-0.86 (m, 5H).

EXAMPLE 40(19)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-hydroxy-3-methylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.85 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.30-7.21 (m,2H), 6.88 (t, J=7.5 Hz, 1H), 4.36 (s, 2H), 4.03 (dd, J 7.8, 4.2 Hz, 1H),3.94-3.78 (m, 2H), 3.56-3.46 (m, 2H), 3.42-3.32 (m, 2H), 2.50-2.30 (m,2H), 2.28 (s, 3H), 2.28-2.06 (m, 2H), 1.82-1.01 (m, 15H), 1.00-0.87 (m,5H).

EXAMPLE 40(20)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-chlorophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.57 (d, J=8.7Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 4.36 (s, 2H), 4.03 (dd, J=7.5, 4.8 Hz,1H), 3.89-3.71 (m, 2H), 3.53-3.33 (m, 4H), 2.52-2.32 (m, 2H), 2.26-2.07(m, 2H), 1.83-1.06 (m, 15H), 1.04-0.84 (m, 2H), 0.95 (t, J=6.9 Hz, 3H).

EXAMPLE 40(21)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(7-methoxy-1,3-benzodioxolan-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=20:1); NMR (CD₃OD): δ 6.85 (s, 1H),6.74 (s, 1H), 5.99 (s, 2H), 4.25 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H),3.92 (s, 3H), 3.87-3.67 (m, 2H), 3.54-3.34 (m, 4H), 2.53-2.30 (m, 2H),2.25-2.05 (m, 2H), 1.83-1.10 (m, 15H), 1.06-0.83 (m, 2H), 0.95 (t, J=7.2Hz, 3H).

EXAMPLE 40(22)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-methyl-4-methoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.37-7.28 (m,2H), 6.99 (d, J=8.1 Hz, 1H), 4.25 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H),3.85 (s, 3H), 3.84-3.66 (m, 2H), 3.52-3.32 (m, 4H), 2.48-2.28 (m, 2H),2.22 (s, 3H), 2.22-2.05 (m, 2H), 1.83-1.10 (m, 15H), 1.06-0.83 (m, 2H),0.94 (t, J=6.9 Hz, 3H).

EXAMPLE 40(23)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-fluorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.53 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.18-7.00 (m, 6H), 4.33 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H),3.87-3.69 (m, 2H), 3.55-3.32 (m, 4H), 2.52-2.32 (m, 2H), 2.28-2.08 (m,2H), 1.83-1.12 (m, 15H), 1.06-0.83 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 40(24)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-trifluoromethoxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.72-7.69 (m,2H), 7.41 (d, J=7.8 Hz, 2H), 4.40 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H),3.90-3.75 (m, 2H), 3.52-3.38 (m, 4H), 2.54-2.32 (m, 2H), 2.28-2.10 (m,2H), 1.80-1.10 (m, 15H), 1.02-0.88 (m, 5H).

EXAMPLE 40(25)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-methyl-5-chloro-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.56-7.50 (m,5H), 4.33 (s, 2H), 4.05 (dd, J=7.8, 4.5 Hz, 1H), 3.98-3.80 (m, 2H),3.70-3.59 (m, 2H), 3.50-3.40 (m, 2H), 2.60-2.38 (m, 2H), 2.45 (s, 3H), δ2.32-2.14 (m, 2H), 1.82-1.14 (m, 15H), 1.02-0.86 (m, 5H).

EXAMPLE 40(26)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2,3-dimethyl-5-oxo-1-phenylpyrazolin-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.27 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.62-7.48 (m,3H), 7.44-7.38 (m, 2H), 4.13 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H),3.88-3.72 (m, 2H), 3.64-3.52 (m, 2H), 3.50-3.38 (m, 2H), 3.35 (s, 3H),2.60-2.40 (m, 2H), 2.48 (s, 3H), 2.28-2.10 (m, 2H), 1.82-1.10 (m, 15H),1.02-0.84 (m, 5H).

EXAMPLE 40(27)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(1-(2-methylpropyloxycarbonyl)indol-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.26 (d, J=8.4Hz, 1H), 7.82 (s, 1H), 7.76 (d, J=3.6 Hz, 1H), 7.50 (dd, J=8.4, 1.8 Hz,1H), 6.74 (d, J=3.6 Hz, 1H), 4.44 (s, 2H), 4.25 (d, J=6.6 Hz, 2H), 4.03(dd, J=7.8, 4.8 Hz, 1H), 3.86-3.72 (m, 2H), 3.52-3.40 (m, 4H), 2.52-2.36(m, 2H), 2.25-2.06 (m, 3H), 1.80-1.10 (m, 15H), 1.07 (d, J=9.0 Hz, 6H),1.00-0.84 (m, 5H).

EXAMPLE 40(28)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(5-methyl-2-phenyloxazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.04-8.00 (m,2H), 7.51-7.49 (m, 3H), 4.34 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz, 1H),3.98-3.82 (m, 2H), 3.70-3.60 (m, 2H), 3.44-3.38 (m, 2H), 2.52 (s, 3H),2.50-2.36 (m, 2H), 2.28-2.12 (m, 2H), 1.80-1.12 (m, 15H), 1.00-0.86 (m,5H).

EXAMPLE 40(29)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methylsulfonylaminophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.32 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=9.0Hz, 2H), 7.41 (d, J=9.0 Hz, 2H), 4.32 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz,1H), 3.92-3.76 (m, 2H), 3.65-3.58 (m, 2H), 3.52-3.45 (m, 2H), 3.04 (s,3H), 2.64-2.50 (m, 2H), 2.43 (s, 3H), 2.40 (s, 3H), 2.28-2.12 (m, 2H),1.82-1.10 (m, 15H), 1.00-0.88 (m, 5H).

EXAMPLE 40(30)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=9.0Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.08-7.00 (m, 4H), 4.33 (s, 2H), 4.03(dd, J=7.5, 4.8 Hz, 1H), 3.85-3.72 (m, 2H), 3.54-3.36 (m, 4H), 2.95 (s,3H), 2.48-2.34 (m, 2H), 2.25-2.08 (m, 2H), 1.80-1.14 (m, 15H), 0.98-0.88(m, 5H).

EXAMPLE 40(31)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.58 (d, J=2.7Hz, 1H), 8.17 (m, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.75 (d, J=9.0 Hz, 2H),7.30 (d, J=9.0 Hz, 2H), 4.39 (s, 2H), 4.03 (dd, J=7.5, 4.8 Hz, 1H),3.88-3.72 (m, 2H), 3.56-3.44 (m, 4H), 2.76 (s, 3H), 2.68-2.50 (m, 2H),2.24-2.06 (m, 2H), 1.82-1.14 (m, 15H), 1.02-0.88 (m, 5H).

EXAMPLE 40(32)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(6-methylpyridin-1-oxido-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.40 (m, 1H),7.69 (d, J=8.4 Hz, 2H), 7.69 (m, 1H), 7.54 (m, 1H), 7.27 (d, J=8.4 Hz,2H), 4.39 (s, 2H), 4.04 (dd, J=7.5, 4.8 Hz, 1H), 3.88-3.72 (m, 2H),3.58-3.39 (m, 4H), 2.59 (s, 3H), 2.58-2.40 (m, 2H), 2.28-2.06 (m, 2H),1.82-1.10 (m, 15H), 1.02-0.84 (m, 5H).

EXAMPLE 40(33)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.49 (d, J=8.4Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 4.63 (m, 1H), 4.27 (s, 2H), 4.02 (dd,J=7.8, 4.8 Hz, 1H), 3.97-3.90 (m, 2H), 3.84-3.66 (m, 2H), 3.62-3.52 (m,2H), 3.50-3.38 (m, 3H), 2.54-2.38 (m, 2H), 2.22-1.98 (m, 4H), 1.80-1.10(m, 18H), 1.00-0.86 (m, 5H).

EXAMPLE 40(34)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(6-phenylpyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD): δ 9.14 (m, 1H),8.75 (m, 1H), 8.36 (m, 1H), 8.02-7.99 (m, 2H), 7.68-7.62 (m, 3H), 4.63(s, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H), 4.02-3.94 (m, 2H), 3.64-3.42 (m,4H), 2.72-2.56 (m, 2H), 2.25-2.06 (m, 2H), 1.80-1.10 (m, 15H), 1.00-0.86(m, 5H).

EXAMPLE 40(35)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-fluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.58-7.50 (m,2H), 7.37-7.28 (m, 2H), 4.32 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H),3.94-3.73 (m, 2H), 3.67-3.55 (m, 2H), 3.53-3.42 (m, 2H), 2.70-2.48 (m,2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.30-2.08 (m, 2H), 1.84-1.10 (m, 15H),1.08-0.93 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 40(36)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(pyridin-2-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.53 (dd, J=4.8,1.5 Hz, 1H), 8.11-8.00 (m, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.49-7.41 (m,1H), 4.32 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H), 3.95-3.74 (m, 2H),3.66-3.54 (m, 2H), 3.50-3.37 (m, 2H), 2.68 (s, 3H), 2.64-2.40 (m, 2H),2.43 (s, 3H), 2.30-2.08 (m, 2H), 1.93-1.10 (m, 15H), 1.08-0.92 (m, 2H),0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 40(37)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.34 (d, J=9.0Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 4.35 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz,1H), 3.93-3.78 (m, 2H), 3.64-3.61 (m, 2H), 3.50 (t, J=8.0 Hz, 2H),2.68-2.56 (m, 2H), 2.49 (s, 3H), 2.39 (s, 3H), 2.25-2.12 (m, 2H),1.81-1.19 (m, 15H), 0.95 (t, J=7.5 Hz, 3H), 0.99-0.91 (m, 2H).

EXAMPLE 40(38)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(2-carboxyethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.46 (d, J=8.3Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 4.32 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.85-3.74 (m, 2H), 3.50-3.46 (m, 2H), 3.40-3.35 (m, 2H), 2.96 (t,J=7.2 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.42-2.30 (m, 2H), 2.34-2.10 (m,2H), 1.78-1.18 (m, 15H), 0.94 (t, J=7.2 Hz, 3H), 0.94 (m, 2H).

EXAMPLE 40(39)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-hydroxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.4Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0Hz, 2H), 4.30 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.83-3.72 (m, 2H),3.49-3.34 (m, 4H), 2.38 (m, 2H), 2.23-2.10 (m, 2H), 1.78-1.16 (m, 15H),1.02-0.92 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 40(40)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-carboxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.19 (d, J=8.4Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 4.33 (s, 2H), 4.06 (dd, J=7.5, 4.5 Hz,1H), 3.93-3.80 (m, 2H), 3.61 (m, 2H), 3.43-3.38 (m, 2H), 2.44 (s, 3H),2.40 (m, 2H), 2.39 (s, 3H), 2.21 (m, 2H), 1.75-1.18 (m, 15H), 0.96 (m,2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 40(41)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(dimethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.54 (chloroform:methanol=9:1); NMR (CD₃OD): δ 7.96 (d, J=8.7Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.05 (dd, J=7.8, 4.5 Hz,1H), 3.94-3.74 (m, 2H), 3.66-3.56 (m, 2H), 3.48 (m, 2H), 2.74 (s, 6H),2.59 (m, 2H), 2.49 (s, 3H), 2.41 (s, 3H), 2.29-2.10 (m, 2H), 1.84-1.16(m, 13H), 1.06-0.86 (m, 5H).

EXAMPLE 40(42)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(5-methylpyridin-1-oxido-2-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49 (chloroform:methanol=9:1); NMR (CD₃OD): δ 7.77 (brs, 1H),7.61 (d, J=7.5 Hz, 2H), 7.56 (dd, J=9.3, 2.4 Hz, 1H), 7.00 (d, J=7.5 Hz,2H), 6.73 (d, J=9.3 Hz, 1H), 4.34 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz, 1H),3.86-3.69 (m, 2H), 3.52-3.35 (m, 4H), 2.44 (m, 2H), 2.25-2.06 (m, 2H),2.18 (s, 3H), 1.84-1.14 (m, 15H), 1.04-0.96 (m, 5H).

EXAMPLE 40(43)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(2-carboxy-1-ethynyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.17 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.75 (d, J=8.4Hz, 2H), 7.70 (d, J=15.9 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 6.57 (d,J=15.9 Hz, 1H), 4.39 (s, 2H), 4.04 (dd, J=7.2, 4.8 Hz, 1H), 3.90-3.72(m, 2H), 3.58-3.36 (m, 4H), 2.50-2.32 (m, 2H), 2.28-2.08 (m, 2H),1.92-1.10 (m, 15H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 40(44)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-((1E)-2-carboxy-1-ethynyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.69-7.63 (m,3H), 7.57 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.4 Hz,2H), 6.42 (d, J=15.9 Hz, 1H), 4.36 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.90-3.74 (m, 2H), 3.55-3.36 (m, 4H), 2.50-2.30 (m, 2H), 2.30-2.08(m, 2H), 1.82-1.10 (m, 15H), 1.02-0.88 (m, 5H).

EXAMPLE 40(45)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-aminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.90 (d, J=9.0Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0Hz, 2H), 4.36 (s, 2H), 4.04 (dd, J=7.5, 4.5, Hz, 1H), 3.90-3.72 (m, 2H),3.56-3.35 (m, 4H), 2.53-2.35 (m, 2H), 2.28-2.08 (m, 2H), 1.84-1.13 (m,15H), 1.06-0.86 (m, 5H).

EXAMPLE 40(46)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-aminosulfonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (d₆-DMSO): δ 11.03 (brs,1H), 8.42 (brs, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H),7.33 (brs, 2H), 7.16 (d, J=8.7 Hz, 4H), 4.38-4.23 (m, 2H), 3.91 (m, 1H),3.61-3.23 (m, 6H), 2.58-2.30 (m, 2H), 2.18-1.91 (m, 2H), 1.76-1.00 (m,15H), 0.98-0.71 (m, 5H).

EXAMPLE 40(47)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-benzylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.41-7.33 (m,3H), 7.22-7.20 (m, 2H), 5.46 (s, 2H), 4.31 (s, 2H), 4.04 (dd, J=7.5, 4.5Hz, 1H), 3.88-3.74 (m, 2H), 3.58-3.48 (m, 4H), 2.61 (m, 2H), 2.47 (s,6H), 2.24-2.09 (m, 2H), 1.80-1.16 (m, 15H), 0.95 (t, J=7.2 Hz, 3H), 0.95(m, 2H).

EXAMPLE 40(48)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(2,4-difluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.58-7.51 (m,1H), 7.33-7.25 (m, 1H), 7.22-7.16 (m, 1H), 4.31 (s, 2H), 4.05 (dd,J=7.5, 4.5 Hz, 1H), 3.91-3.78 (m, 2H), 3.59 (m, 2H), 3.44 (m, 2H), 2.49(m, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 2.27-2.15 (m, 2H), 1.81-1.16 (m,15H), 0.96 (t, J=7.0 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 40(49)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(pyrrolidin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.14 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.74 (d, J=8.4Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 4.43 (s, 2H), 4.40 (s, 2H), 4.03 (dd,J=7.5, 4.5 Hz, 1H), 3.90-3.70 (m, 2H), 3.56-3.38 (m, 6H), 3.28-3.10 (m,2H), 2.66-2.48 (m, 2H), 2.26-1.92 (m, 6H), 1.83-1.10 (m, 15H), 1.06-0.83(m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 40(50)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(morpholin-4-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.46 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.95 (d, J=8.7Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.05 (dd, J=7.8, 4.5 Hz,1H), 3.94-3.74 (m, 2H), 3.76-3.67 (m, 4H), 3.66-3.56 (m, 2H), 3.56-3.42(m, 2H), 3.10-2.92 (m, 4H), 2.68-2.50 (m, 2H), 2.50 (s, 3H), 2.42 (s,3H), 2.30-2.08 (m, 2H), 1.84-1.08 (m, 15H), 1.08-0.83 (m, 2H), 0.95 (t,J=7.2 Hz, 3H).

EXAMPLE 40(51)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-cyanophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.75 (d, J=9.3Hz, 2H), 7.64 (d, J=9.0 Hz, 2H), 7.22 (d, J=9.0 Hz, 2H), 7.14 (d, J=9.3Hz, 2H), 4.40 (s, 2H), 4.05 (dd, J=7.5, 4.8 Hz, 1H), 3.92-3.74 (m, 2H),3.58-3.36 (m, 4H), 2.52-2.36 (m, 2H), 2.32-2.08 (m, 2H), 1.84-1.12 (m,15H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 40(52)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(N-(2-hydroxyethyl)-N-methylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.68 (chloroform:methanol=5:1); NMR (CD₃OD): δ 8.00 (d, J=8.7Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 4.33 (s, 2H), 4.06 (dd, J=7.5, 4.5 Hz,1H), 3.86-3.76 (m, 2H), 3.70 (t, J=5.7 Hz, 2H), 3.68-3.60 (m, 2H),3.58-3.42 (m, 2H), 3.20 (t, J=5.7 Hz, 2H), 2.88 (s, 3H), 2.72-2.58 (m,2H), 2.50 (s, 3H), 2.44 (s, 3H), 2.28-2.06 (m, 2H), 1.82-1.10 (m, 15H),0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 40(53)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(2-phenylethyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.24 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.28-7.23 (m,3H), 7.10-7.07 (m, 2H), 4.40 (t, J=6.6 Hz, 2H), 4.19 (s, 2H), 4.06 (dd,J=7.2, 4.8 Hz, 1H), 3.80-3.60 (m, 2H), 3.58-3.36 (m, 4H), 3.12 (t, J=6.6Hz, 2H), 2.64-2.45 (m, 2H), 2.45 (s, 3H), 2.26-2.04 (m, 2H), 1.95 (s,3H), 1.84-1.14 (m, 15H), 0.97 (t, J=7.5 Hz, 3H), 0.97 (m, 2H).

EXAMPLE 40(54)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(dimethylaminomethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.16 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.76 (d, J=8.1Hz, 2H), 7.63 (d, J=8.1 Hz, 2H), 4.41 (s, 2H), 4.37 (s, 2H), 4.03 (dd,J=7.8, 5.1 Hz, 1H), 3.90-3.75 (m, 2H), 3.52-3.38 (m, 4H), 2.87 (s, 6H),2.64-2.48 (m, 2H), 2.22-2.04 (m, 2H), 1.80-1.15 (m, 15H), 1.00-0.86 (m,5H).

EXAMPLE 40(55)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-(4-hydroxyphenyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.58 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.81 (s, 1H),7.69 (d, J=7.5 Hz, 1H), 7.54 (d, J=9.0 Hz, 2H), 7.55-7.48 (m, 1H), 7.45(d, J=7.5 Hz, 1H), 6.87 (d, J=9.0 Hz, 2H), 4.40 (s, 2H), 4.03 (dd,J=7.5, 4.5 Hz, 1H), 3.92-3.73 (m, 2H), 3.58-3.43 (m, 2H), 3.43-3.32 (m,2H), 2.55-2.35 (m, 2H), 2.28-2.06 (m, 2H), 1.82-1.10 (m, 15H), 1.08-0.83(m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 40(56)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(quinoxalin-2-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.67 (chloroform:methanol=10:1); NMR (CD₃OD): δ 9.51 (s, 1H),8.13 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.91-7.80 (m, 2H), 4.38(s, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H), 3.96-3.82 (m, 2H), 3.63 (m, 2H),3.42 (m, 2H), 2.92 (s, 3H), 2.47 (s, 3H), 2.47 (m, 2H), 2.29-2.16 (m,2H), 1.80-1.18 (m, 15H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (m, 2H).

EXAMPLE 40(57)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(phenylcarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.68 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.87 (d, J=8.4Hz, 2H), 7.82-7.74 (m, 4H), 7.67 (t, J=8.4 Hz, 1H), 7.57-7.51 (m, 2H),4.48 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz, 1H), 3.84-3.78 (m, 2H), 3.58-3.38(m, 4H), 2.58-2.40 (m, 2H), 2.30-2.10 (m, 2H), 1.82-1.14 (m, 15H),1.02-0.86 (m, 5H).

EXAMPLE 40(58)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methylaminosulfonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.30 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.01 (d, J=8.7Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 4.33 (s, 2H), 4.06 (dd, J=7.8, 4.5 Hz,1H), 3.86-3.78 (m, 2H), 3.68-3.58 (m, 2H), 3.52-3.36 (m, 2H), 2.59 (s,3H), 2.59-2.38 (m, 2H), 2.48 (s, 3H), 2.41 (s, 3H), 2.34-2.10 (m, 2H),1.84-1.16 (m, 15H), 0.97 (t, J=7.2 Hz, 3H), 0.97 (m, 2H).

EXAMPLE 40(59)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(1,3,5-trimethylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 4.28 (s, 2H),4.03 (dd, J=7.8, 4.5 Hz, 1H), 3.87 (s, 3H), 3.87-3.69 (m, 2H), 3.61-3.43(m, 4H), 2.69-2.50 (m, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.25-2.06 (m,2H), 1.83-1.12 (m, 15H), 1.05-0.86 (m, 5H).

EXAMPLE 40(60)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(morpholin-4-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.56 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.74 (d, J=8.4Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 4.40 (s, 4H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 4.00-3.70 (m, 6H), 3.54-3.40 (m, 4H), 3.35-3.18 (m, 4H), 2.63-2.47(m, 2H), 2.24-2.02 (m, 2H), 1.83-1.12 (m, 15H), 1.06-0.85 (m, 5H).

EXAMPLE 40(61)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(3-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.28 (t, J=8.4 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 6.75 (ddd,J=8.4, 2.4, 1.0 Hz, 1H), 6.61-6.57 (m, 2H), 4.34 (s, 2H), 4.04 (dd,J=7.5, 4.5 Hz, 1H), 3.85-3.55 (m, 2H), 3.77 (s, 3H), 3.53-3.47 (m, 2H),3.40 (m, 2H), 2.50-2.35 (m, 2H), 2.25-2.11 (m, 2H), 1.80-1.23 (m, 15H),0.95 (t, J=7.2 Hz, 3H), 0.95 (m, 2H).

EXAMPLE 40(62)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylpiperazin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.69 (chloroform:methanol=5:1); NMR (CD₃OD): δ 7.74 (s, 4H),4.54 (s, 2H), 4.41 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.87-3.42 (m,14H), 3.00 (s, 3H), 2.61-2.46 (m, 2H), 2.21-2.07 (m, 2H), 1.79-1.15 (m,15H), 1.02-0.92 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 40(63)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(pyridin-1-oxido-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.42 (chloroform:methanol=9:1); NMR (CD₃OD): δ 8.45 (t, J=1.8Hz, 1H), 8.37 (brd, J=6.3 Hz, 1H), 7.71 (dd, J=8.4, 6.3 Hz, 1H), 7.72(d, J=8.7 Hz, 2H), 7.59 (brdd, J=8.4, 1.8 Hz, 1H), 7.31 (d, J=8.7 Hz,2H), 4.40 (s, 2H), 4.04 (dd, J=7.8 Hz, 1H), 3.90-3.74 (m, 2H), 3.57-3.40(m, 4H), 2.58-2.40 (m, 2H), 2.28-2.08 (m, 2H), 1.82-1.14 (m, 15H),1.04-0.90 (m, 5H).

EXAMPLE 40(64)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-phenylsulfonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.77 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 8.08 (d, J=8.4Hz, 2H), 8.02-7.96 (m, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.70-7.55 (m, 3H),4.43 (s, 2H), 4.02 (dd, J=7.8, 4.8 Hz, 1H), 3.89-3.73 (m, 2H), 3.49-3.34(m, 4H), 2.48-2.33 (m, 2H), 2.23-2.04 (m, 2H), 1.82-1.14 (m, 15H),1.03-0.85 (m, 5H).

EXAMPLE 40(65)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.32 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 4.42-4.28 (m,1H), 4.28 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.90-3.72 (m, 2H),3.60-3.43 (m, 4H), 2.68-2.50 (m, 2H), 2.50 (s, 3H), 2.46 (s, 3H),2.25-2.06 (m, 2H), 2.04-1.15 (m, 25H), 1.05-0.89 (m, 5H).

EXAMPLE 40(66)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(3-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.16 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 7.83 (ddd,J=7.8, 1.5, 1.2 Hz, 1H), 7.60 (dd, J=2.4, 1.5 Hz, 1H), 7.57 (d, J=8.7Hz, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.29 (ddd, J=7.8, 2.4, 1.2 Hz, 1H),7.12 (d, J=8.7 Hz, 2H), 4.35 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H),3.90-3.74 (m, 2H), 3.58-3.35 (m, 4H), 2.49-2.34 (m, 2H), 2.28-2.09 (m,2H), 1.93-1.10 (m, 15H), 1.07-0.85 (m, 5H).

EXAMPLE 40(67)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(piperidin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.56 (chloroform:methanol=9:1); NMR (CD₃OD): δ 7.75 (d, J=8.4Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 4.40 (s, 2H), 4.34 (s, 2H), 4.03 (dd,J=7.8, 4.8 Hz, 1H), 3.90-3.72 (m, 2H), 3.53-3.38 (m, 6H), 3.05-2.91 (m,2H), 2.66-2.49 (m, 2H), 2.24-2.04 (m, 2H), 2.00-1.13 (m, 21H), 1.04-0.86(m, 5H).

EXAMPLE 40(68)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.40 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 8.01 (d, J=8.7Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz,1H), 3.94-3.75 (m, 2H), 3.66-3.56 (m, 2H), 3.49-3.41 (m, 2H), 3.32-3.25(m, 4H), 2.60-2.46 (m, 2H), 2.48 (s, 3H), 2.40 (s, 3H), 2.30-2.11 (m,2H), 1.83-1.14 (m, 19H), 1.05-0.87 (m, 5H).

EXAMPLE 40(69)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2,3-dihydrobenzofuran-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.61 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 7.39 (d, J=1.8Hz, 1H), 7.26 (dd, J=8.4, 1.8 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 4.59 (t,J=8.7 Hz, 2H), 4.26 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz, 1H), 3.84-3.67 (m,2H), 3.54-3.34 (m, 4H), 3.25 (t, J=8.7 Hz, 2H), 2.48-2.31 (m, 2H),2.26-2.07 (m, 2H), 1.83-1.14 (m, 15H), 1.04-0.87 (m, 5H).

EXAMPLE 40(70)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (ethyl acetate:methanol=9:1); NMR (CD₃OD): δ 8.04 (d, J=8.7Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.38 (s, 2H), 4.05 (dd, J=7.8, 4.8 Hz, 1H), 3.91-3.74 (m, 2H),3.57-3.35 (m, 4H), 2.50-2.33 (m, 2H), 2.29-2.09 (m, 2H), 1.84-1.14 (m,15H), 1.05-0.86 (m, 5H).

EXAMPLE 40(71)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.03 (d, J=8.7Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz,1H), 3.94-3.74 (m, 2H), 3.66-3.56 (m, 2H), 3.56 (t, J=5.7 Hz, 2H),3.51-3.41 (m, 2H), 3.01 (t, J=5.7 Hz, 2H), 2.63-2.43 (m, 2H), 2.47 (s,3H), 2.40 (s, 3H), 2.32-2.10 (m, 2H), 1.93-1.10 (m, 15H), 1.06-0.93 (m,2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 40(72)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-dimethylaminoethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3 hydrochloride

TLC: Rf 0.13 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.07 (d, J=8.7Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.04 (dd, J=7.5, 4.2 Hz,1H), 3.82-3.76 (m, 2H), 3.68-3.48 (m, 4H), 3.34-3.24 (m, 4H), 2.95 (s,6H), 2.76-2.52 (m, 2H), 2.50 (s, 3H), 2.43 (s, 3H), 2.25-2.08 (m, 2H),1.82-1.14 (m, 15H), 1.02-0.88 (m, 5H).

EXAMPLE 40(73)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(1-hydroxy-1-phenylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.30 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.62-7.18 (m,9H), 5.82 (s, 1H), 4.34 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.88-3.72(m, 2H), 3.58-3.30 (m, 4H), 2.42-2.04 (m, 4H), 1.82-1.24 (m, 15H), 0.94(t, J=7.2 Hz, 3H), 0.94 (m, 2H).

EXAMPLE 40(74)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(carboxymethyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.30 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.7Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 4.70 (s, 2H), 4.29 (s, 2H), 4.03 (dd,J=7.5, 4.5 Hz, 1H), 3.86-3.69 (m, 2H), 3.54-3.33 (m, 4H), 2.44-2.28 (m,2H), 2.26-2.06 (m, 2H), 1.83-1.12 (m, 15H), 1.04-0.85 (m, 5H).

EXAMPLE 40(75)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-hydroxypiperidin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.17 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.76 (d, J=7.8Hz, 2H), 7.70-7.61 (m, 2H), 4.40 (s, 2H), 4.38-4.32 (m, 2H), 4.10-4.05(m, 1H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.90-3.68 (m, 2H), 3.56-3.40 (m,4H), 3.18-3.00 (m, 1H), 2.70-2.48 (m, 2H), 2.23-1.82 (m, 5H), 1.82-1.10(m, 19H), 1.06-0.83 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 40(76)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(3-carboxyphenylmethyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=5:1); NMR (CD₃OD): δ 8.10 (s, 1H),7.98 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H),7.46 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H), 5.22 (s, 2H), 4.28 (s,2H), 4.04 (dd, J=7.8, 4.8 Hz, 1H), 3.84-3.68 (m, 2H), 3.52-3.32 (m, 4H),2.42-2.08 (m, 4H), 1.82-1.16 (m, 15H), 0.95 (t, J=7.8 Hz, 3H), 0.95 (m,2H).

EXAMPLE 40(77)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(1,4-benzodioxan-6-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.48 (d, J=9.0Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 6.86 (m, 1H), 6.55-6.51 (m, 2H), 4.31(s, 2H), 4.24 (s, 4H), 4.05 (dd, J=7.5, 4.5 Hz, 1H), 3.86-3.70 (m, 2H),3.58-3.36 (m, 4H), 2.42-2.08 (m, 4H), 1.82-1.12 (m, 15H), 0.96 (t, J=7.2Hz, 3H), 0.96 (m, 2H).

EXAMPLE 40(78)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-(3-hydroxyphenyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.24 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.81 (s, 1H),7.74 (m, 1H), 7.60-7.50 (m, 2H), 7.28 (m, 1H), 7.15-7.08 (m, 2H), 6.82(m, 1H), 4.43 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.86-3.78 (m, 2H),3.58-3.34 (m, 4H), 2.48-2.08 (m, 4H), 1.84-1.12 (m, 15H), 0.95 (t, J=7.2Hz, 3H), 0.95 (m, 2H).

EXAMPLE 40(79)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(methylsulfonylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.4Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz,1H), 3.86-3.72 (m, 2H), 3.52-3.34 (m, 4H), 3.01 (s, 3H), 2.50-2.32 (m,2H), 2.24-2.06 (m, 2H), 1.82-1.10 (m, 15H), 1.02-0.86 (m, 5H).

EXAMPLE 40(80)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(6-(4-methoxyphenyl)pyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.67 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.26 (m, 1H),8.02 (m, 1H), 7.08-6.84 (m, 5H), 4.38 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz,1H), 3.90-3.72 (m, 2H), 3.81 (s, 3H), 3.56-3.44 (m, 2H), 3.42-3.32 (m,2H), 2.50-2.30 (m, 2H), 2.30-2.08 (m, 2H), 1.82-1.14 (m, 15H), 1.02-0.88(m, 5H).

EXAMPLE 40(81)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.39 (br d,J=4.5 Hz, 1H), 7.84 (d, J=9.0 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.15 (d,J=8.4 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.35 (s, 2H), 4.04 (m, 1H),3.85-3.74 (m, 2H), 3.53-3.38 (m, 4H), 2.91 (d, J=4.5 Hz, 3H), 2.55-2.30(m, 2H), 2.30-2.10 (m, 2H), 1.80-1.10 (m, 15H), 1.10-0.90 (m, 2H), 0.95(t, J=7.2 Hz, 3H).

EXAMPLE 40(82)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-chlorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.76 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=9.0Hz, 2H), 7.38 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0Hz, 2H), 4.32 (s, 2H), 4.04 (m, 1H), 3.90-3.70 (m, 2H), 3.60-3.30 (m,4H), 2.50-2.10 (m, 4H), 1.90-1.10 (m, 15H), 1.10-0.90 (m, 2H), 0.95 (t,J=7.5 Hz, 3H).

EXAMPLE 40(83)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-bis(methylsulfonyl)aminophenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=5:1); NMR (CD₃OD): δ 7.69 (d, J=8.4Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 4.41 (s, 2H), 4.05 (dd, J=7.8, 4.8 Hz,1H), 3.92-3.70 (m, 2H), 3.56-3.36 (m, 4H), 3.47 (s, 6H), 2.46-2.08 (m,4H), 1.84-1.16 (m, 15H), 0.96 (t, J=7.5 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 40(84)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3-(4-carboxyphenyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=5:1); NMR (CD₃OD): δ 8.13 (d, J=9.0Hz, 2H), 7.95 (s, 1H), 7.84 (m, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.66-7.61(m, 2H), 4.46 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.96-3.78 (m, 2H),3.62-3.36 (m, 4H), 2.54-2.32 (m, 2H), 2.28-2.08 (m, 2H), 1.82-1.08 (m,15H), 0.95 (t, J=7.2 Hz, 3H), 0.95 (m, 2H).

EXAMPLE 40(85)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(phenylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.07 (d, J=8.1Hz, 2H), 7.73-7.67 (m, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.38 (t, J=7.5 Hz,2H), 7.17 (t, J=7.5 Hz, 1H), 4.45 (s, 2H), 4.05 (dd, J=7.8, 4.8 Hz, 1H),3.92-3.72 (m, 2H), 3.58-3.36 (m, 4H), 2.50-2.08 (m, 4H), 1.84-1.08 (m,15H), 0.96 (t, J=7.8 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 40(86)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylthiophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54 (d, J=8.7Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7Hz, 2H), 4.34 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H), 3.86-3.70 (m, 2H),3.56-3.36 (m, 4H), 2.48 (s, 3H), 2.48-2.32 (m, 2H), 2.28-2.08 (m, 2H),1.82-1.14 (m, 15H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 40(87)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(2-dimethylaminoethylaminocarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.11 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.94 (d, J=9.0Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.10 (d, J=9.0Hz, 2H), 4.36 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz, 1H), 3.88-3.72 (m, 4H),3.52-3.36 (m, 6H), 2.98 (s, 6H), 2.62-2.44 (m, 2H), 2.24-2.08 (m, 2H),1.80-1.10 (m, 15H), 1.00-0.88 (m, 5H).

EXAMPLE 40(88)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-aminocarbonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.19 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.98 (d, J=8.4Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 4.43 (s, 2H), 4.03 (dd, J=7.5, 4.8 Hz,1H), 3.92-3.76 (m, 2H), 3.54-3.28 (m, 4H), 2.52-2.36 (m, 2H), 2.24-2.08(m, 2H), 1.82-1.10 (m, 15H), 1.02-0.88 (m, 5H).

EXAMPLE 40(89)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(dimethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.67 (d, J=8.1Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 4.41 (s, 2H), 4.04 (dd, J=7.5, 4.2 Hz,1H), 3.92-3.76 (m, 2H), 3.54-3.32 (m, 4H), 3.11 (s, 3H), 2.99 (s, 3H),2.52-2.32 (m, 2H), 2.26-2.08 (m, 2H), 1.82-1.10 (m, 15H), 1.02-0.86 (m,5H).

EXAMPLE 40(90)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane

TLC: Rf 0.73 (chloroform:methanol=10:1); NMR (CDCl₃): δ 7.37-7.25 (m,4H), 7.10 (m, 1H), 7.04-6.98 (m, 2H), 6.96 (d, J=8.7 Hz, 2H), 5.81 (brs,1H), 3.99 (m, 1H), 3.52 (s, 2H), 3.52-3.32 (m, 2H), 2.92-2.74 (m, 3H),2.57 (dt, J=12.0, 3.0 Hz, 1H), 2.18-1.88 (m, 5H), 1.76-1.13 (m, 14H),1.07-0.88 (m, 2H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 41 By the same procedure as described in Reference Example3→Reference Example 4 using Resin (3) prepared in Reference Example 2,N-allyloxycarbonyl-4-piperidone, n-butylamine and(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoicacid, and furthermore by the same procedure as described in ReferenceExample 5→Reference Example 6→Example 1 using1,4-benzodioxan-6-carboxyaldehyde, the following compounds (1) and (2)of the present invention were obtained respectively. EXAMPLE 41(1)1-butyl-2,5-dioxo-3-(1-hydroxy-2-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

(Symbol * means the mixture of syn form and anti form (syn:anti=2:3.)

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.1Hz, 1H), 6.97 (dd, J=8.4, 2.1 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.26 (s,4H), 4.23 (s, 2H), 4.13 (d, J=2.1 Hz, 0.6H), 4.08 (d, J=1.2 Hz, 0.4H),4.05-3.90 (m, 1H), 3.76-3.63 (m, 1H), 3.62-3.35 (m, 3.4H), 3.19 (dd,J=9.6, 2.1 Hz, 0.6H), 3.20-3.10 (m, 1H), 2.55-2.33 (m, 2H), 2.30-1.95(m, 3H), 1.80-1.60 (m, 1H), 1.55-1.25 (m, 3H), 1.05-0.89 (m, 9H).

EXAMPLE 41(2)(Z)-1-butyl-2,5-dioxo-3-(2-methylpropylidene)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.04 (d, J=2.1Hz, 1H), 6.97 (dd, J=8.4, 2.1 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 5.84 (d,J=10.5 Hz, 1H), 4.26 (s, 4H), 4.23 (s, 2H), 3.72-3.55 (m, 2H), 3.53-3.35(m, 4H), 2.80-2.60 (m, 1H), 2.43-2.26 (m, 2H), 2.25-2.15 (m, 2H),1.62-1.48 (m, 2H), 1.45-1.30 (m, 2H), 1.04 (d, J=6.6 Hz, 6H), 0.95 (t,J=7.5 Hz, 3H).

EXAMPLE 41(3) TO 41(5)

By the same procedure as described in Example 41 using the correspondingcompounds instead of(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoicacid, and the corresponding compounds instead of1,4-benzodioxan-6-carboxyaldehyde, the following compounds of thepresent invention were obtained.

EXAMPLE 41(3)(3S)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxyethyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.54 (d, J=8.7Hz, 2H), 7.43-7.35 (m, 2H), 7.21-7.14 (m, 1H), 7.08-7.00 (m, 4H), 4.32(s, 2H), 4.19 (dq, J=1.5, 6.9 Hz, 1H), 4.10-3.97 (m, 1H), 3.78 (d, J=1.5Hz, 1H), 3.72-3.51 (m, 2H), 3.51-3.40 (m, 2H), 3.28-3.14 (m, 1H),2.57-2.42 (m, 2H), 2.40-2.25 (m, 1H), 2.21-2.10 (m, 1H), 1.81-1.60 (m,1H), 1.50-1.30 (m, 3H), 1.22 (d, J=6.9 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 41(4)(Z)-1-butyl-2,5-dioxo-3-ethylidene-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.29 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.53 (d, J=9.0Hz, 2H), 7.43-7.35 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.09-7.00 (m, 4H),6.08 (q, J=7.5 Hz, 1H), 4.33 (s, 2H), 3.76-3.61 (m, 2H), 3.57-3.40 (m,4H), 2.45-2.30 (m, 2H), 2.28-2.15 (m, 2H), 1.77 (d, J=7.5 Hz, 3H),1.62-1.46 (m, 2H), 1.44-1.28 (m, 2H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 41(5)(Z)-1-butyl-2,5-dioxo-3-(2-methylpropylidene)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.42 (chloroform:methanol=20:1); NMR (CD₃OD): δ 7.51 (d, J=8.7Hz, 2H), 7.43-7.35 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.06 (d, J=8.7 Hz,2H), 7.08-7.01 (m, 2H), 5.85 (d, J=10.5 Hz, 1H), 4.34 (s, 2H), 3.78-3.64(m, 2H), 3.57-3.40 (m, 4H), 2.78-2.62 (m, 1H), 2.43-2.18 (m, 4H),1.62-1.48 (m, 2H), 1.46-1.30 (m, 2H), 1.04 (d, J=6.6 Hz, 6H), 0.96 (t,J=7.5 Hz, 3H).

EXAMPLE 42(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 35 using(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoicacid instead of N-(t-butyloxycarbonyl)-L-leucine, the compound of thepresent invention having the following physical data was obtained.

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.39-7.30 (m,5H), 5.13 (br, 2H), 4.12 (d, J=2.5 Hz, 1H), 4.10-4.00 (m, 2H), 3.76-3.50(m, 2H), 3.39-3.25 (m, 2H), 3.10-2.94 (m, 1H), 2.18 (m, 1H), 2.08-1.83(m, 4H), 1.70-1.56 (m, 1H), 1.45-1.15 (m, 3H), 1.01-0.89 (m, 9H).

EXAMPLE 43(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 9 using the compoundprepared in Example 42, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.08 (chloroform:methanol=10:1); NMR (CD₃OD): δ 4.15 (d, J=2.0Hz, 1H), 3.96 (dt, J=13.0, 4.0 Hz, 1H), 3.71 (dt, J=13.0, 4.0 Hz, 1H),3.57-3.47 (m, 1H), 3.40-3.34 (m, 2H), 3.23-3.12 (m, 2H), 2.47-2.30 (m,2H), 2.25-1.98 (m, 3H), 1.79-1.66 (m, 1H), 1.52-1.28 (m, 3H), 1.07-0.94(m, 9H).

EXAMPLE 44(1) TO 44(13)

By the same procedure as described in Example 10 using the compoundprepared in Example 43 and the corresponding aldehyde derivatives, thefollowing compounds were obtained.

EXAMPLE 44(1)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=8.7Hz, 2H), 7.44-7.35 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10-7.00 (m, 4H),4.33 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.06-3.93 (m, 1H), 3.80-3.67 (m,1H), 3.56-3.40 (m, 3H), 3.19 (dd, J=9.3, 2.1 Hz, 1H), 3.20-3.10 (m, 1H),2.53-2.35 (m, 2H), 2.35-2.20 (m, 1H), 2.19-2.08 (m, 1H), 2.07-1.91 (m,1H), 1.80-1.70 (m, 1H), 1.50-1.25 (m, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 44(2)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.60-7.45 (m,5H), 4.30 (s, 2H), 4.15 (d, J=2.4 Hz, 1H), 4.05 (m, 1H), 3.79 (m, 1H),3.62-3.48 (m, 3H), 3.29-3.16 (m, 2H), 2.60-2.45 (m, 2H), 2.44-2.30 (m,7H), 2.17 (m, 1H), 2.01 (m, 1H), 1.70 (m, 1H), 1.51-1.31 (m, 3H),1.03-0.91 (m, 9H).

EXAMPLE 44(3)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(6-phenyloxypyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.39 (d, J=2.1Hz, 1H), 8.16 (dd, J=8.4, 2.1 Hz, 1H), 7.46 (t, J=7.8 Hz, 2H), 7.29 (t,J=7.8 Hz, 1H), 7.17 (d, J=7.8 Hz, 2H), 7.08 (d, J=8.4 Hz, 1H), 4.40 (s,2H), 4.13 (d, J=2.1 Hz, 1H), 4.07-3.94 (m, 1H), 3.83-3.69 (m, 1H),3.60-3.42 (m, 3H), 3.29-3.22 (m, 1H), 3.19 (dd, J=9.6, 2.1 Hz, 1H),2.62-2.32 (m, 3H), 2.18-2.07 (m, 1H), 2.06-1.94 (m, 1H), 1.78-1.60 (m,1H), 1.50-1.31 (m, 3H), 1.07-0.87 (m, 9H).

EXAMPLE 44(4)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.7Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7Hz, 2H), 4.29 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 3.97 (m, 1H), 3.72 (m,1H), 3.56-3.39 (m, 2H), 3.25-3.09 (m, 3H), 2.53-2.08 (m, 7H), 2.01 (m,1H), 1.70 (m, 1H), 1.48-1.28 (m, 3H), 1.05-0.88 (m, 9H).

EXAMPLE 44(5)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-cyclohexyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40 (d, J=8.7Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 4.37 (m, 1H), 4.24 (brs, 2H), 4.13 (d,J=2.1 Hz, 1H), 3.94 (m, 1H), 3.68 (m, 1H), 3.52-3.34 (m, 2H), 3.29-3.07(m, 3H), 2.52-1.92 (m, 7H), 1.85-1.27 (m, 12H), 1.04-0.89 (m, 9H).

EXAMPLE 44(6)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-(tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.20 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 7.45 (d,J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 4.67-4.59 (m, 1H), 4.28 (s, 2H),4.13 (d, J=2.5 Hz, 1H), 4.00-3.90 (m, 3H), 3.75-3.67 (m, 1H), 3.63-3.53(m, 2H), 3.50-3.41 (m, 3H), 3.18 (dd, J=9.0, 2.0 Hz, 1H), 3.18 (m, 1H),2.49-1.96 (m, 7H), 1.77-1.65 (m, 3H), 1.44-1.30 (m, 3H), 0.98 □ (d,J=6.5 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 44(7)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-(pyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.22 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 8.76 (d,J=2.5 Hz, 1H), 8.63 (d, J=6.0 Hz, 1H), 8.29 (dd, J=9.0, 2.5 Hz, 1H),8.08 (dd, J=9.0, 6.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0 Hz,2H), 4.41 (s, 2H), 4.14 (d, J=2.0 Hz, 1H), 4.00 (m, 1H), 3.76 (m, 1H),3.61-3.47 (m, 3H), 3.20 (dd, J=9.5, 2.0 Hz, 1H), 3.20 (m, 1H), 2.62 (m,1H), 2.46 (m, 2H), 2.10 (m, 1H), 2.05-1.95 (m, 1H), 1.69 (m, 1H),1.41-1.35 (m, 3H), 0.99 (d, J=6.5 Hz, 3H), 0.97 (d, J=6.5 Hz, 3H), 0.95(t, J=7.5 Hz, 3H).

EXAMPLE 44(8)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-isopropylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.1Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 4.31 (s, 2H), 4.13 (d, J=2.1 Hz, 1H),4.05-3.91 (m, 1H), 3.80-3.65 (m, 1H), 3.57-3.38 (m, 3H), 3.26-3.13 (m,1H), 3.19 (dd, J=9.3, 2.1 Hz, 1H), 3.03-2.86 (m, 1H), 2.53-2.38 (m, 2H),2.38-2.23 (m, 1H), 2.16-2.05 (m, 1H), 2.06-1.92 (m, 1H), 1.77-1.56 (m,1H), 1.49-1.26 (m, 3H), 1.25 (d, J=6.9 Hz, 6H), 0.98 (d, J=6.6 Hz, 3H),0.97 (d, J=6.6 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 44(9)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40 (s, 4H),4.33 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.11-3.97 (m, 1H), 3.86-3.72 (m,1H), 3.64-3.50 (m, 3H), 3.39-3.30 (m, 1H), 3.21 (dd, J=9.3, 2.1 Hz, 1H),2.72-2.55 (m, 1H), 2.53-2.40 (m, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.40(s, 3H), 2.18-2.07 (m, 1H), 2.07-1.96 (m, 1H), 1.78-1.60 (m, 1H),1.50-1.30 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.95(t, J=7.2 Hz, 3H).

EXAMPLE 44(10)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(3-methyl-5-chloro-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.56 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.58-7.47 (m,5H), 4.33 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.15-4.02 (m, 1H), 3.89-3.75(m, 1H), 3.65-3.48 (m, 3H), 3.30-3.20 (m, 1H), 3.20 (dd, J=9.6, 2.1 Hz,1H), 2.64-2.46 (m, 2H), 2.44 (s, 3H), 2.44-2.32 (m, 1H), 2.21-2.10 (m,1H), 2.08-1.93 (m, 1H), 1.80-1.60 (m, 1H), 1.52-1.30 (m, 3H), 0.99 (d,J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 44(11)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.29 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.04 (d, J=9.0Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.7 Hz, 2H), 7.07 (d, J=9.0Hz, 2H), 4.37 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.10-3.94 (m, 1H),3.83-3.69 (m, 1H), 3.59-3.40 (m, 3H), 3.25-3.12 (m, 1H), 3.19 (dd,J=9.3, 2.1 Hz, 1H), 2.55-2.37 (m, 2H), 2.37-2.22 (m, 1H), 2.19-2.08 (m,1H), 2.08-1.94 (m, 1H), 1.79-1.60 (m, 1H), 1.52-1.26 (m, 3H), 0.99 (d,J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 44(12)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(pyridin-2-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.53 (d, J=5.1Hz, 1H), 8.05 (t, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.44 (dd,J=7.8, 5.1 Hz, 1H), 4.33 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.06 (m, 1H),3.78 (m, 1H), 3.62-3.44 (m, 3H), 3.26 (m, 1H), 3.21 (dd, J=9.6, 2.1 Hz,1H), 2.68 (s, 3H), 2.60-2.30 (m, 3H), 2.42 (s, 3H), 2.16 (m, 1H), 2.02(m, 1H), 1.72 (m, 1H), 1.50-1.26 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.99(d, J=6.6 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 44(13)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-carboxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.25 (chloroform:methanol:acetic acid=20:2:1); NMR (CD₃OD): δ8.19 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.16 (d,J=2.1 Hz, 1H), 4.12-3.98 (m, 1H), 3.87-3.74 (m, 1H), 3.63-3.45 (m, 3H),3.30-3.10 (m, 1H), 3.20 (dd, J=9.3, 2.1 Hz, 1H), 2.59-2.48 (m, 2H), 2.44(s, 3H), 2.40-2.23 (m, 1H), 2.39 (s, 3H), 2.23-2.10 (m, 1H), 2.10-1.96(m, 1H), 1.80-1.62 (m, 1H), 1.52-1.24 (m, 3H), 1.00 (d, J=6.6 Hz, 3H),0.98 (d, J=6.6 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 45(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 35 using(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-3-cyclohexylpropanoicacid instead of N-(t-butyloxycarbonyl)-L-leucine, the compound of thepresent invention having the following physical data was obtained.

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.39-7.27 (m,5H), 5.13 (m, 2H), 4.13 (d, J=2.5 Hz, 1H), 4.06-4.02 (m, 2H), 3.78-3.48(m, 2H), 3.36-3.29 (m, 2H), 3.02 (br, 1H), 2.17 (m, 1H), 2.03-1.58 (m,10H), 1.47-1.13 (m, 6H), 1.02-0.89 (m, 5H).

EXAMPLE 46(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Example 9 using the compoundprepared in Example 45, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.33 (chloroform:methanol:acetic acid=20:6:1); NMR (CD₃OD): δ4.13 (d, J=2.5 Hz, 1H), 3.48-3.22 (m, 5H), 2.97-2.89 (m, 2H), 2.12-1.65(m, 10H), 1.56-1.16 (m, 7H), 1.03-0.85 (m, 5H).

EXAMPLE 47(1) TO 47(8)

By the same procedure as described in Example 10 using the compoundprepared in Example 46 and the corresponding aldehyde compounds, thefollowing compounds of the present invention were obtained.

EXAMPLE 47(1)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.55-7.51 (m,2H), 7.42-7.36 (m, 2H), 7.18 (tt, J=7.5, 1.0 Hz, 1H), 7.08-7.01 (m, 4H),4.32 (s, 2H), 4.15 (d, J=2.0 Hz, 1H), 3.98 (dt, J=3.5, 12.5 Hz, 1H),3.73 (dt, J=3.5, 12.5 Hz, 1H), 3.57-3.39 (m, 3H), 3.26 (d, J=2.0 Hz,1H), 3.20 (m, 1H), 2.52-2.39 (m, 2H), 2.30 (m, 1H), 2.12 (d, J=15.5 Hz,1H), 2.04-1.92 (m, 2H), 1.80-1.62 (m, 5H), 1.48-1.11 (m, 6H), 1.01-0.82(m, 5H).

EXAMPLE 47(2)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.60-7.50 (m,5H), 4.33 (s, 2H), 4.17 (d, J=2.5 Hz, 1H), 4.04 (m, 1H), 3.85-3.75 (m,1H), 3.61-3.51 (m, 3H), 3.35-3.27 (m, 2H), 2.62 (m, 1H), 2.49-2.44 (m,5H), 2.41 (s, 3H), 2.15 (m, 1H), 2.05-1.92 (m, 2H), 1.77-1.65 (m, 5H),1.44-1.15 (m, 6H), 1.01-0.85 (m, 5H).

EXAMPLE 47(3)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-isopropylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.69 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.48 (d, J=8.4Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.14 (d, J=2.1 Hz, 1H),3.98 (m, 1H), 3.72 (m, 1H), 3.55-3.40 (m, 3H), 3.29-3.16 (m, 2H), 2.95(m, 1H), 2.52-2.24 (m, 3H), 2.15-1.86 (m, 3H), 1.80-1.60 (m, 5H),1.48-1.10 (m, 6H), 1.25 (d, J=6.9 Hz, 6H), 1.02-0.82 (m, 5H).

EXAMPLE 47(4)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.51 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 8.59 (d,J=2.7 Hz, 1H), 8.19 (dd, J=9.0, 2.7 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H),7.75 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 4.39 (s, 2H), 4.15 (d,J=2.0 Hz, 1H), 3.99 (m, 1H), 3.73 (m, 1H), 3.61-3.46 (m, 3H), 3.37-3.26(m, 2H), 2.77 (s, 3H), 2.62 (m, 1H), 2.45 (m, 1H), 2.13-1.92 (m, 3H),1.73 (m, 4H), 1.40-1.14 (m, 8H), 1.01-0.86 (m, 2H), 0.95 (t, J=7.0 Hz,3H).

EXAMPLE 47(5)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-fluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.49 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 7.57 (m, 2H),7.37-7.31 (m, 2H), 4.32 (s, 2H), 4.16 (d, J=2.0 Hz, 1H), 4.08-4.00 (m,1H), 3.79 (m, 1H), 3.63-3.52 (m, 3H), 3.37-3.27 (m, 2H), 2.65 (m, 1H),2.48 (m, 1H), 2.45 (s, 3H), 2.39 (s, 3H), 2.16-1.92 (m, 3H), 1.73 (m,4H), 1.42-1.15 (m, 8H), 1.01-0.88 (m, 2H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 47(6)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=9.0Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.99-6.92 (m, 4H), 4.30 (s, 2H), 4.16(d, J=2.1 Hz, 1H), 3.98 (m, 1H), 3.80 (s, 3H), 3.72 (m, 1H), 3.58-3.38(m, 3H), 3.30-3.08 (m, 2H), 2.54-1.88 (m, 6H), 1.82-1.60 (m, 5H),1.50-1.10 (m, 6H), 0.96 (t, J=7.5 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 47(7)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-fluorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.51 (d, J=8.7Hz, 2H), 7.13 (d, J=8.7 Hz, 2H), 7.10-7.04 (m, 4H), 4.33 (s, 2H), 4.16(d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.72 (m, 1H), 3.58-3.40 (m, 3H),3.30-3.08 (m, 2H), 2.56-1.88 (m, 6H), 1.82-1.60 (m, 5H), 1.54-1.10 (m,6H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (m, 2H).

EXAMPLE 47(8)(3R*)-1-butyl-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 7.53 (d,J=8.1 Hz, 2H), 7.30 (d, J=9.0 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.04 (d,J=9.0 Hz, 2H), 4.34 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.76(m, 1H), 3.58-3.42 (m, 3H), 3.30-3.08 (m, 2H), 2.96 (s, 3H), 2.54-1.88(m, 6H), 1.82-1.62 (m, 5H), 1.50-1.14 (m, 6H), 0.96 (t, J=7.2 Hz, 3H),0.96 (m, 2H).

EXAMPLE 48(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-allyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Reference Example 3→ReferenceExample 6→Example 1 using Resin (3) prepared in Reference Example 2,N-allyloxycarbonyl-4-piperidone, 2-butynylamine, and(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-3-cyclohexylpropanoicacid, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.32 (chloroform:methanol=15:1); NMR (CD₃OD): δ 6.04-5.91 (m,1H), 5.35-5.27 (m, 1H), 5.23-5.19 (m, 1H), 4.60-4.58 (m, 2H), 4.27 (dq,J=17.5, 2.5 Hz, 1H), 4.19 (d, J=2.5 Hz, 1H), 4.07-4.01 (m, 2H), 3.89(dq, J=17.5, 2.5 Hz, 1H), 3.75-3.50 (m, 2H), 3.38 (dd, J=9.0, 2.5 Hz,1H), 2.32-2.17 (m, 2H), 2.07-1.70 (m, 11H), 1.33-1.14 (m, 3H), 1.00-0.85(m, 2H).

EXAMPLE 49(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Reference Example 4 using thecompound prepared in Example 48, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.33 (chloroform:methanol:acetic acid=20:6:1); NMR (CD₃OD): δ4.28 (dq, J=17.5, 2.5 Hz, 1H), 4.18 (d, J=2.5 Hz, 1H), 4.03 (dq, J=17.5,2.5 Hz, 1H), 3.48-3.29 (m, 3H), 2.99-2.90 (m, 2H), 2.26-1.73 (m, 14H),1.32-1.18 (m, 3H), 1.01-0.91 (m, 2H).

EXAMPLE 50(1) TO 50(6)

By the same procedure as described in Example 10 using the compoundprepared in Example 49 and the corresponding aldehyde compounds, thefollowing compounds of the present invention were obtained.

EXAMPLE 50(1)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.37 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.60-7.50 (m,5H), 4.42-4.33 (m, 3H), 4.21 (d, J=2.5 Hz, 1H), 4.08-3.99 (m, 2H),3.85-3.75 (m, 1H), 3.65-3.57 (m, 2H), 3.32 (m, 1H), 2.79 (m, 1H),2.48-2.43 (m, 5H), 2.40 (s, 3H), 2.22 (m, 1H), 2.05-1.93 (m, 2H),1.80-1.64 (m, 7H), 1.39-1.11 (m, 3H), 1.03-0.84 (m, 2H).

EXAMPLE 50(2)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40 (s, 4H),4.45-4.30 (m, 3H), 4.20 (m, 1H), 4.16-3.98 (m, 2H), 3.78 (m, 1H),3.68-3.56 (m, 2H), 3.30 (m, 1H), 2.82 (m, 1H), 2.56-2.42 (m, 8H), 2.39(s, 3H), 2.28-1.88 (m, 3H), 1.80-1.60 (m, 7H), 1.40-1.10 (m, 3H),1.12-0.82 (m, 2H).

EXAMPLE 50(3)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-isopropylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.1Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 4.38-4.28 (m, 3H), 4.17 (m, 1H),4.04-3.88 (m, 2H), 3.74 (m, 1H), 3.50-3.40 (m, 2H), 3.28 (m, 1H), 2.92(m, 1H), 2.64 (m, 1H), 2.50-1.86 (m, 5H), 1.80-1.62 (m, 7H), 1.36-1.04(m, 3H), 1.25 (d, J=7.2 Hz, 6H), 1.00-0.82 (m, 2H).

EXAMPLE 50(4)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=9.0Hz, 2H), 7.42-7.37 (m, 2H), 7.17 (t, J=7.5 Hz, 1H), 7.06-7.02 (m, 4H),4.40-4.30 (m, 3H), 4.18 (m, 1H), 4.04-3.90 (m, 2H), 3.72 (m, 1H),3.30-3.20 (m, 2H), 3.28 (m, 1H), 2.68 (m, 1H), 2.52-1.86 (m, 5H),1.80-1.60 (m, 7H), 1.38-1.10 (m, 3H), 1.02-0.82 (m, 2H).

EXAMPLE 50(5)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50 (d, J=8.4Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.4Hz, 2H), 4.40-4.28 (m, 3H), 4.18 (m, 1H), 4.04-3.88 (m, 2H), 3.74 (m,1H), 3.52-3.40 (m, 2H), 3.26 (m, 1H), 2.64 (m, 1H), 2.54-1.86 (m, 5H),2.33 (s, 3H), 1.80-1.62 (m, 7H), 1.38-1.10 (m, 3H), 1.02-0.82 (m, 2H).

EXAMPLE 50(6)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-1-cyclohexylmethyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (s, 1H),6.99-6.91 (m, 2H), 4.35 (m, 1H), 4.27 (s, 4H), 4.24 (s, 2H), 4.18 (m,1H), 4.04-3.84 (m, 2H), 3.70 (m, 1H), 3.56-3.38 (m, 2H), 3.28 (m, 1H),2.68-1.88 (m, 6H), 1.80-1.60 (m, 7H), 1.40-1.10 (m, 3H), 1.02-0.80 (m,2H).

EXAMPLE 51(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.acetate

By the same procedure as described in Example 48→Example 49 using(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoicacid instead of(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-3-cyclohexylpropanoicacid, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.22 (chloroform:methanol:acetic acid=20:6:1); NMR (CD₃OD): δ4.36 (dq, J=17.0, 2.5 Hz, 1H), 4.19 (d, J=2.0 Hz, 1H), 3.95-3.79 (m,2H), 3.62 (dt, J=3.5, 13.0 Hz, 1H), 3.34-3.26 (m, 2H), 3.22 (dd, J=9.5,2.0 Hz, 1H); 2.54-2.43 (m, 1H), 2.37 (m, 1H), 2.20-1.98 (m, 3H), 1.91(s, 3H), 1.75 (t, J=2.5 Hz, 3H), 1.01-0.97 (m, 6H).

EXAMPLE 52(1) TO 52(5)

By the same procedure as described in Example 10 using the compoundprepared in Example 51 and the corresponding aldehyde compounds, thefollowing compounds of the present invention were obtained.

EXAMPLE 52(1)

(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.38 (d, J=3.9Hz, 2H), 7.35 (d, J=3.9 Hz, 2H), 4.33 (s, 2H), 4.20 (d, J=2.1 Hz, 1H),4.10-3.90 (m, 2H), 3.78 (m, 1H), 3.68-3.52 (m, 2H), 3.22 (dd, J=9.3, 2.1Hz, 1H), 2.74 (m, 1H), 2.54-2.20 (m, 3H), 2.44 (s, 3H), 2.40 (s, 3H),2.36 (s, 3H), 1.98 (m, 1H), 1.75 (t, J=2.1 Hz, 3H), 1.01 (d, J=6.6 Hz,3H), 0.99 (d, J=6.6 Hz, 3H).

EXAMPLE 52(2)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.26 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.49 (d, J=9.0Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 6.93 (d, J=8.4Hz, 2H), 4.40 (m, 1H), 4.34 (s, 2H), 4.19 (d, J=2.1 Hz, 1H), 4.08-3.82(m, 2H), 3.76 (m, 1H), 3.58-3.40 (m, 2H), 3.20 (dd, J=9.6, 2.1 Hz, 1H),2.72-2.42 (m, 2H), 2.35 (s, 3H), 2.35-2.18 (m, 2H), 2.00 (m, 1H), 1.74(t, J=2.1 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H).

EXAMPLE 52(3)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06-6.92 (m,3H), 4.38 (m, 1H), 4.28 (s, 4H), 4.25 (s, 2H), 4.19 (d, J=2.1 Hz, 1H),4.02-3.84 (m, 2H), 3.70 (m, 1H), 3.52-3.36 (m, 2H), 3.20 (dd, J=9.6, 2.1Hz, 1H), 2.60 (m, 1H), 2.48 (m, 1H), 2.32-2.16 (m, 2H), 2.00 (m, 1H),1.74 (t, J=2.1 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H).

EXAMPLE 52(4)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-isopropylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.29 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.47 (d, J=8.1Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.40 (m, 1H), 4.33 (s, 2H), 4.19 (d,J=2.1 Hz, 1H), 4.08-3.84 (m, 2H), 3.76 (m, 1H), 3.52-3.40 (m, 2H), 3.20(dd, J=9.6, 2.1 Hz, 1H), 2.96 (m, 1H), 2.62 (m, 1H), 2.48 (m, 1H),2.36-2.12 (m, 2H), 2.00 (m, 1H), 1.74 (t, J=2.1 Hz, 3H), 1.24 (d, J=7.2Hz, 6H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H).

EXAMPLE 52(5)(3R*)-1-(2-butynyl)-2,5-dioxo-3-((1R*)-1-hydroxy-2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.24 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=9.0Hz, 2H), 7.41 (t, J=7.2 Hz, 2H), 7.19 (t, J=7.2 Hz, 1H), 7.09-7.03 (m,4H), 4.40 (m, 1H), 4.35 (s, 2H), 4.19 (d, J=2.1 Hz, 1H), 4.08-3.84 (m,2H), 3.78 (m, 1H), 3.58-3.42 (m, 2H), 3.21 (dd, J=9.6, 2.1 Hz, 1H),2.72-2.42 (m, 2H), 2.38-2.18 (m, 2H), 2.00 (m, 1H), 1.74 (t, J=2.1 Hz,3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H).

EXAMPLE 53(3R*)-1-butyl-2,5-dioxo-3-((1S*)-1-hydroxy-1-cyclohexylmethyl)-9-benzyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Reference Example 3→ReferenceExample 6→Example 1 using Resin (3) prepared in Reference Example 2,N-benzyl-4-piperidone, n-butylamine,(2R*,3S*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-3-cyclohexylpropanoicacid, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.40-7.20 (m,5H), 4.04 (d, J=1.5 Hz, 1H), 3.65-3.45 (m, 2H), 3.57 (s, 2H), 3.30 (m,1H), 3.05 (m 1H), 2.86-2.77 (m, 3H), 2.30-2.00 (m, 4H), 1.90-1.60 (m,6H), 1.60-1.10 (m, 9H), 1.10-0.90 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 54(3R*)-1-butyl-2,5-dioxo-3-((1S*)-1-hydroxy-1-cyclohexylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 9 using the compoundprepared in Example 53, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.59 (chloroform:methanol:acetic acid=10:2:1); NMR (CD₃OD): δ4.08 (d, J=1.5 Hz, 1H), 4.03 (m, 1H), 3.70-3.12 (m, 7H), 2.50-2.02 (m,5H), 1.85-1.66 (m, 5H), 1.55-1.10 (m, 7H), 1.10-0.85 (m, 2H), 0.97 (t,J=6.9 Hz, 3H).

EXAMPLE 55(1) TO 55(3)

By the same procedure as described in Example 10 using the compoundprepared in Example 54 and the corresponding aldehyde compounds, thefollowing compounds of the present invention were obtained.

EXAMPLE 55(1)(3R*)-1-butyl-2,5-dioxo-3-((1S*)-1-hydroxy-1-cyclohexylmethyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50 (d, J=8.7Hz, 2H), 7.39 (dd, J=8.7, 7.5 Hz, 2H), 7.17 (t, J=7.5 Hz, 1H), 7.09-7.00(m, 4H), 4.30 (brs, 2H), 4.08 (d, J=1.2 Hz, 1H), 4.04 (m, 1H), 3.74-3.36(m, 5H), 3.16 (m, 1H), 2.55-2.33 (m, 2H), 2.32-2.09 (m, 2H), 2.04 (m,1H), 1.84-1.61 (m, 5H), 1.53-1.12 (m, 7H), 1.04-0.86 (m, 5H).

EXAMPLE 55(2)(3R*)-1-butyl-2,5-dioxo-3-((1S*)-1-hydroxy-1-cyclohexylmethyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.04 (d, J=2.1Hz, 1H), 6.97 (dd, J=8.1, 2.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.26 (s,4H), 4.21 (s, 2H), 4.07 (d, J=1.2 Hz, 1H), 4.01 (m, 1H), 3.70-3.34 (m,5H), 3.16 (m, 1H), 2.53-2.32 (m, 2H), 2.31-2.08 (m, 2H), 2.03 (m, 1H),1.84-1.60 (m, 5H), 1.52-1.12 (m, 7H), 1.04-0.85 (m, 5H).

EXAMPLE 55(3)(3R*)-1-butyl-2,5-dioxo-3-((1S*)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.31 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.44 (m,5H), 4.31 (s, 2H), 4.19-4.06 (m, 2H), 3.73 (m, 1H), 3.66-3.52 (m, 4H),3.26 (m, 1H), 2.62-2.48 (m, 2H), 2.45-2.30 (m, 7H), 2.19 (m, 1H), 2.04(m, 1H), 1.84-1.63 (m, 5H), 1.54-1.12 (m, 7H), 1.05-0.86 (m, 5H).

EXAMPLE 56(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 42→Example 43 using(2S,3S)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoic acidinstead of(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoicacid, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.08 (chloroform:methanol=10:1); NMR (CD₃OD): δ 4.15 (d, J=2.0Hz, 1H), 3.96 (dt, J=13.0, 4.0 Hz, 1H), 3.71 (dt, J=13.0, 4.0 Hz, 1H),3.57-3.47 (m, 1H), 3.40-3.34 (m, 2H), 3.23-3.12 (m, 2H), 2.47-2.30 (m,2H), 2.25-1.98 (m, 3H), 1.79-1.66 (m, 1H), 1.52-1.28 (m, 3H), 1.07-0.94(m, 9H); Optical rotation: [α]_(D)−13.8 (c 1.00, methanol).

EXAMPLE 57(1) TO 57(4)

By the same procedure as described in Example 10 using the compoundprepared in Example 56 and the corresponding aldehyde compounds, thefollowing compounds of the present invention were obtained.

EXAMPLE 57(1)(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5;5]undecane.2hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.43 (m,5H), 4.32 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.12-3.99 (m, 1H), 3.90-3.72(m, 1H), 3.64-3.44 (m, 3H), 3.30-3.12 (m, 1H), 3.20 (dd, J=9.3, 2.1 Hz,1H), 2.60-2.30 (m, 9H), 2.24-2.10 (m, 1H), 2.10-1.95 (m, 1H), 1.78-1.60(m, 1H), 1.54-1.30 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz,3H), 0.96 (t, J=6.9 Hz, 3H).

EXAMPLE 57(2)(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=8.7Hz, 2H), 7.43-7.36 (m, 2H), 7.21-7.14 (m, 1H), 7.10-7.00 (m, 4H), 4.33(s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.06-3.92 (m, 1H), 3.81-3.66 (m, 1H),3.58-3.40 (m, 3H), 3.30-3.10 (m, 1H), 3.19 (dd, J=9.6, 2.1 Hz, 1H),2.53-2.37 (m, 2H), 2.37-2.18 (m, 1H), 2.18-2.08 (m, 1H), 2.06-1.95 (m,1H), 1.78-1.60 (m, 1H), 1.50-1.26 (m, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 57(3)(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06 (d, J=2.1Hz, 1H), 6.98 (dd, J=8.1, 2.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.26 (s,4H), 4.23 (s, 2H), 4.13 (d, J=2.4 Hz, 1H), 4.02-3.87 (m, 1H), 3.77-3.62(m, 1H), 3.57-3.35 (m, 3H), 3.28-3.08 (m, 1H), 3.19 (dd, J=9.6, 2.4 Hz,1H), 2.51-2.35 (m, 2H), 2.35-2.18 (m, 1H), 2.17-2.05 (m, 1H), 2.05-1.90(m, 1H), 1.80-1.58 (m, 1H), 1.50-1.26 (m, 3H), 0.98 (d, J=6.6 Hz, 3H),0.97 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 57(4)(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.10-7.00 (m, 4H), 4.33 (s, 2H), 4.14(d, J=2.1 Hz, 1H), 4.06-3.92 (m, 1H), 3.81-3.66 (m, 1H), 3.58-3.40 (m,3H), 3.25-3.10 (m, 1H), 3.19 (dd, J=9.6, 2.1 Hz, 1H), 2.95 (s, 3H),2.54-2.37 (m, 2H), 2.37-2.22 (m, 1H), 2.18-2.08 (m, 1H), 2.08-1.92 (m,1H), 1.78-1.60 (m, 1H), 1.50-1.28 (m, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 58(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 42→Example 43 using(2R,3R)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoic acidinstead of(2R*,3R*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoicacid, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.08 (chloroform:methanol=10:1); NMR (CD₃OD): δ 4.15 (d, J=2.0Hz, 1H), 3.96 (dt, J=13.0, 4.0 Hz, 1H), 3.71 (dt, J=13.0, 4.0 Hz, 1H),3.57-3.47 (m, 1H), 3.40-3.34 (m, 2H), 3.23-3.12 (m, 2H), 2.47-2.30 (m,2H), 2.25-1.98 (m, 3H), 1.79-1.66 (m, 1H), 1.52-1.28 (m, 3H), 1.07-0.94(m, 9H); Optical rotation: [α]_(D)+13.9 (c 1.00, methanol).

EXAMPLE 59(1) TO 59(4)

By the same procedure as described in Example 10 using the compoundprepared in Example 58 and the corresponding aldehyde compounds, thefollowing compounds of the present invention were obtained.

EXAMPLE 59(1)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.61-7.43 (m,5H), 4.32 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.12-3.99 (m, 1H), 3.90-3.72(m, 1H), 3.64-3.44 (m, 3H), 3.30-3.12 (m, 1H), 3.20 (dd, J=9.3, 2.1 Hz,1H), 2.60-2.30 (m, 9H), 2.24-2.10 (m, 1H), 2.10-1.95 (m, 1H), 1.78-1.60(m, 1H), 1.54-1.30 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz,3H), 0.96 (t, J=6.9 Hz, 3H).

EXAMPLE 59(2)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.52 (d, J=8.7Hz, 2H), 7.43-7.36 (m, 2H), 7.21-7.14 (m, 1H), 7.10-7.00 (m, 4H), 4.33(s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.06-3.92 (m, 1H), 3.81-3.66 (m, 1H),3.58-3.40 (m, 3H), 3.30-3.10 (m, 1H), 3.19 (dd, J=9.6, 2.1 Hz, 1H),2.53-2.37 (m, 2H), 2.37-2.18 (m, 1H), 2.18-2.08 (m, 1H), 2.06-1.95 (m,1H), 1.78-1.60 (m, 1H), 1.50-1.26 (m, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 59(3)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06 (d, J=2.1Hz, 1H), 6.98 (dd, J=8.1, 2.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.26 (s,4H), 4.23 (s, 2H), 4.13 (d, J=2.4 Hz, 1H), 4.02-3.87 (m, 1H), 3.77-3.62(m, 1H), 3.57-3.35 (m, 3H), 3.28-3.08 (m, 1H), 3.19 (dd, J=9.6, 2.4 Hz,1H), 2.51-2.35 (m, 2H), 2.35-2.18 (m, 1H), 2.17-2.05 (m, 1H), 2.05-1.90(m, 1H), 1.80-1.58 (m, 1H), 1.50-1.26 (m, 3H), 0.98 (d, J=6.6 Hz, 3H),0.97 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 59(4)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.10-7.00 (m, 4H), 4.33 (s, 2H), 4.14(d, J=2.1 Hz, 1H), 4.06-3.92 (m, 1H), 3.81-3.66 (m, 1H), 3.58-3.40 (m,3H), 3.25-3.10 (m, 1H), 3.19 (dd, J=9.6, 2.1 Hz, 1H), 2.95 (s, 3H),2.54-2.37 (m, 2H), 2.37-2.22 (m, 1H), 2.18-2.08 (m, 1H), 2.08-1.92 (m,1H), 1.78-1.60 (m, 1H), 1.50-1.28 (m, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 60(3R)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 53→Example 54 using(2R,3S)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoic acidinstead of(2R*,3S*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-3-cyclohexylpropanoicacid, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.51 (chloroform:methanol:acetic acid=10:2:1); NMR (CD₃OD): δ4.08 (d, J=1.5 Hz, 1H), 4.02 (dt, J=12.6, 3.9 Hz, 1H), 3.70-3.00 (m,6H), 2.50-2.10 (m, 4H), 1.80-1.60 (m, 2H), 1.55-1.35 (m, 3H), 1.02 (d,J=6.6 Hz, 3H), 0.99 (t, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H); Opticalrotation: [α]_(D)+21.2 (c 1.00, methanol).

EXAMPLE 61(1) TO 61(3)

By the same procedure as described in Example 10 using the compoundprepared in Example 60 and the corresponding aldehyde compounds, thefollowing compounds of the present invention were obtained.

EXAMPLE 61 (1)(3R)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.64-7.46 (m,5H), 4.32 (s, 2H), 4.19-4.06 (m, 1H), 4.10 (d, J=1.5 Hz, 1H), 3.80-3.53(m, 4H), 3.51 (dd, J=10.2, 1.5 Hz, 1H), 3.40-3.20 (m, 1H), 2.70-2.30 (m,9H), 2.23-2.10 (m, 1H), 1.83-1.60 (m, 2H), 1.53-1.30 (m, 3H), 1.02 (d,J=6.6 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 61(2)(3R)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06 (d, J=2.1Hz, 1H), 6.98 (dd, J=8.1, 2.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.26 (s,4H), 4.23 (s, 2H), 4.08 (d, J=1.5 Hz, 1H), 4.08-3.96 (m, 1H), 3.72-3.35(m, 4H), 3.49 (dd, J=10.2, 1.5 Hz, 1H), 3.28-3.08 (m, 1H), 2.55-2.35 (m,2H), 2.35-2.18 (m, 1H), 2.18-2.08 (m, 1H), 1.82-1.62 (m, 2H), 1.52-1.25(m, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.92 (d, J=6.6Hz, 3H).

EXAMPLE 61(3)(3R)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.03 (d, J=9.0Hz, 2H), 4.33 (s, 2H), 4.13-4.00 (m, 1H), 4.09 (d, J=1.5 Hz, 1H),3.75-3.62 (m, 1H), 3.62-3.39 (m, 3H), 3.49 (dd, J=10.5, 1.5 Hz, 1H),3.26-3.12 (m, 1H), 2.95 (s, 3H), 2.56-2.37 (m, 2H), 2.37-2.20 (m, 1H),2.20-2.10 (m, 1H), 1.82-1.63 (m, 2H), 1.50-1.30 (m, 3H), 1.01 (d, J=6.6Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).

EXAMPLE 62(3S)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 53→Example 54 using(2S,3R)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-4-methylpentanoic acidinstead of(2R*,3S*)-N-(t-butyloxycarbonyl)-2-amino-3-hydroxy-3-cyclohexylpropanoicacid, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.51 (chloroform:methanol:acetic acid=10:2:1); NMR (CD₃OD): δ4.08 (d, J=1.5 Hz, 1H), 4.02 (dt, J=12.6, 3.9 Hz, 1H), 3.70-3.00 (m,6H), 2.50-2.10 (m, 4H), 1.80-1.60 (m, 2H), 1.55-1.35 (m, 3H), 1.02 (d,J=6.6 Hz, 3H), 0.99 (t, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H); Opticalrotation: [α]_(D)−23.4 (c 1.00, methanol).

EXAMPLE 63(1) TO 63(3)

By the same procedure as described in Example 10 using the compoundprepared in Example 62 and the corresponding aldehyde compounds, thefollowing compounds of the present invention were obtained.

EXAMPLE 63(1)(3S)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.64-7.46 (m,5H), 4.32 (s, 2H), 4.19-4.06 (m, 1H), 4.10 (d, J=1.5 Hz, 1H), 3.80-3.53(m, 4H), 3.51 (dd, J=10.2, 1.5 Hz, 1H), 3.40-3.20 (m, 1H), 2.70-2.30 (m,9H), 2.23-2.10 (m, 1H), 1.83-1.60 (m, 2H), 1.53-1.30 (m, 3H), 1.02 (d,J=6.6 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 63(2)(3S)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.06 (d, J=2.1Hz, 1H), 6.98 (dd, J=8.1, 2.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.26 (s,4H), 4.23 (s, 2H), 4.08 (d, J=1.5 Hz, 1H), 4.08-3.96 (m, 1H), 3.72-3.35(m, 4H), 3.49 (dd, J=10.2, 1.5 Hz, 1H), 3.28-3.08 (m, 1H), 2.55-2.35 (m,2H), 2.35-2.18 (m, 1H), 2.18-2.08 (m, 1H), 1.82-1.62 (m, 2H), 1.52-1.25(m, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.92 (d, J=6.6Hz, 3H).

EXAMPLE 63(3)(3S)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=8.7Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.03 (d, J=9.0Hz, 2H), 4.33 (s, 2H), 4.13-4.00 (m, 1H), 4.09 (d, J=1.5 Hz, 1H),3.75-3.62 (m, 1H), 3.62-3.39 (m, 3H), 3.49 (dd, J=10.5, 1.5 Hz, 1H),3.26-3.12 (m, 1H), 2.95 (s, 3H), 2.56-2.37 (m, 2H), 2.37-2.20 (m, 1H),2.20-2.10 (m, 1H), 1.82-1.63 (m, 2H), 1.50-1.30 (m, 3H), 1.01 (d, J=6.6Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).

EXAMPLE 64(3S)-2,5-dioxo-3-(3-benzyloxycarbonylaminopropyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Reference Example 9→ReferenceExample 10→Example 1 using Resin (3) prepared in Reference Example 2,N-(2-phenylethyl)-4-piperidone, 2,4,6-trimethoxybenzylamine andN^(α)-(t-butyloxycarbonyl)-Nδ-(benzyloxycarbonyl)-L-ornithine, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (DMSO-d₆): δ 10.80-10.00(m, 1H), 8.65-8.45 (m, 1H), 8.33 (s, 1H), 7.50-7.20 (m, 10H), 5.01 (s,2H), 4.01 (m, 1H), 3.70-3.45 (m, 3H), 3.45-3.20 (m, 3H), 3.15-2.90 (m,4H), 2.50-2.30 (m, 2H), 2.10-1.90 (m, 1H), 1.87-1.60 (m, 3H), 1.60-1.35(m, 2H).

EXAMPLE 65(3S)-1-methyl-2,5-dioxo-3-(3-benzyloxycarbonylaminopropyl)-9-(2-phenylethyl)-1,4,9-triazaspiro[5.5]undecane.acetate

By the same procedure as described in Example 19 using Resin (3)prepared in Reference Example 2, N-(2-phenylethyl)-4-piperidone,methylamine andN^(α)-(t-butyloxycarbonyl)-N^(δ)-(benzyloxycarbonyl)-L-ornithine, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.36 (chloroform:methanol=10:1); MS (ESI, Pos., 40 V):493(M+H)⁺; HPLC condition: F; HPLC retention time: 3.36 min.

EXAMPLE 66(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-phenyloxyphenylmethyl)-9-oxido-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Example 40(90) (104 mg) inacetone (4 ml) were added water (1 ml), sodium hydrogen carbonate (210mg) and OXONE (615 mg) (brand name). The reaction mixture was stirredfor 1 hour at room temperature. The reaction mixture was diluted withethyl acetate, washed with saturated aqueous solution of sodium hydrogencarbonate, and saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby preparative thin layer chromatography (chloroform:methanol=30:1,20:1) to give the compound of the present invention (73 mg) having thefollowing physical data.

TLC: Rf 0.50 (chloroform:methanol=9:1); NMR (CDCl₃): δ 7.49 (dt, J=8.7,2.1 Hz, 2H), 7.36 (ddt, J=8.7, 7.2, 2.1 Hz, 2H), 7.14 (tt, J=7.2, 1.2Hz, 1H), 7.04 (dq, J=8.7, 1.2 Hz, 2H), 7.01 (dt, J=8.7, 2.1 Hz, 2H),5.82 (brs, 1H), 4.32 (s, 2H), 4.07-3.85 (m, 3H), 3.55-3.46 (m, 2H),3.19-2.97 (m, 4H), 2.02-1.49 (m, 11H), 1.48-1.12 (m, 6H), 1.08-0.90 (m,2H), 0.90 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 13(2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methyl-N-butyl-N-[4-benzylaminocarbonyl-1-benzylpiperidin-4-yl]pentanamide

To a solution of(2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid (10.5g) in methanol (340 ml) was added n-butylamine (4.2 ml),N-benzyl-4-piperidone (7.9 ml) and benzylisonitrile (5.2 ml). Thereaction mixture was stirred overnight at 55° C. The reaction mixturewas concentrated. The obtained residue was purified by columnchromatography on silica gel (chloroform:methanol=100:1→75:1→50:1) togive the title compound (19.8 g) having the following physical data.

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.38-7.15 (m,10H), 4.58 (d, J=9.6 Hz, 1H), 4.39 (d, J=15.0 Hz, 1H), 4.23 (d, J=15.0Hz, 1H), 3.70-3.30 (m, 3H), 3.50 (s, 2H), 2.79-2.30 (m, 6H), 2.08-1.88(m, 2H), 1.88-1.70 (m, 3H), 1.50-1.28 (m, 2H), 1.38 (s, 9H), 0.98 (t,J=7.2 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H).

REFERENCE EXAMPLE 14(2R,3R)-2-amino-3-hydroxy-4-methyl-N-butyl-N-[4-benzylaminocarbonyl-1-benzyl-piperidin-4-yl]pentanamide

To a solution of the compound (19.8 g) prepared in Reference example 13in dichloromethane (65 ml) was added trifluoroacetic acid (50 ml) underice bath. The reaction mixture was stirred for 1 hr at room temperature.To the reaction mixture was added dichloromethane, neutrified withaqueous solution of sodium carbonate and extracted. The extract waswashed with water and saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate and concentrated to give the titlecompound having the following physical data. The obtained residue wasused in the next reaction without further purification.

TLC:Rf 0.38 (chloroform:methanol=10:1).

EXAMPLE 67(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-propyl)-9-benzyl-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Reference example 14 intoluene (200 ml) was added acetic acid (15 ml). The reaction mixture wasstirred for 45 minutes at 80° C. The reaction mixture was diluted withethyl acetate, neutrified with aqueous solution of sodium carbonate andextracted. The extract was washed with saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate and concentrated.The obtained residue purified by column chromatography on silica gel(ethyl acetate:methanol=25:1) to give the title compound (12.9 g) havingthe following physical data.

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.36-7.22 (m,5H), 4.10 (d, J=2.7 Hz, 1H), 3.60 (s, 2H), 3.47 (m, 1H), 3.38-3.25 (m,2H), 2.96 (m, 1H), 2.87-2.73 (m, 3H), 2.25-1.94 (m, 4H), 1.82 (m, 1H),1.64 (m, 1H), 1.53-1.27 (m, 3H), 0.96 (d, J=6.6 Hz, 6H), 0.95 (t, J=7.5Hz, 3H).

REFERENCE EXAMPLE 15(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

Under an atmosphere of argon, to a solution of the compound (12.67 g)prepared in Example 67 in methanol (160 ml) was added 20% palladiumhydroxide on carbon (1.3 g). Under an atmosphere of hydrogen, thereaction mixture was stirred for 12 hours at room temperature. Thereaction mixture was filtrated with Celite (brand name) and the filtratewas concentrated. The obtained residue was purified by columnchromatography on silica gel(chloroform:hexane=3:1→chloroform:methanol=100:1→50:1→30:1→20:1→10:1).The obtained compound was added 4N hydrogen chloride/ethyl acetatesolution and concentrated to give the title compound (8.6 g) having thefollowing physical data.

TLC: Rf 0.16 (chloroform:methanol:acetic acid=20:4:1); NMR (CD₃OD): δ4.15 (d, J=2.1 Hz, 1H), 3.95 (m, 1H), 3.71 (m, 1H), 3.52 (m, 1H),3.42-3.31 (m, 2H), 3.21 (m, 1H), 3.21 (dd, J=9.6, 2.1 Hz, 1H), 2.48-2.32(m, 2H), 2.23 (m, 1H), 2.14-1.96 (m, 2H), 1.72 (m, 1H), 1.55-1.33 (m,3H), 1.02-0.92 (m, 9H); Optical rotation: [α]_(D)+13.9 (c 1.00,methanol, 28° C.).

REFERENCE EXAMPLE 15(1) TO 15(9)

By the same procedure described in Reference example 13→Referenceexample 14→Example 67→Reference example 15 using the corresponding aminoacid derivatives respectively instead of(2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid,using the corresponding amine derivatives respectively instead ofn-butylamine, the following compounds were obtained.

REFERENCE EXAMPLE 15(1)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.18 (chloroform:methanol=4:1); NMR (CD₃OD): δ 4.02 (dd, J=7.8,4.6 Hz, 1H), 3.82-3.70 (m, 2H), 3.39 (m, 4H), 2.34-2.09 (m, 4H),1.88-1.50 (m, 5H), 1.37 (m, 2H), 0.97 (t, J=7.5 Hz, 3H), 0.95 (d, J=6.5Hz, 3H), 0.94 (d, J=6.5 Hz, 3H); Optical rotation:[α]_(D)−38.8 (c 1.04,methanol, 23° C.).

REFERENCE EXAMPLE 15(2)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.08 (chloroform:methanol:acetic acid=90:10:1); NMR (CD₃OD): δ4.05 (dd, J=7.8, 4.8 Hz, 1H), 3.84-3.68 (m, 2H), 3.46-3.34 (m, 4H),2.40-2.04 (m, 4H), 1.83-1.46 (m, 10H), 1.39 (sextet, J=7.5 Hz, 2H),1.05-0.86 (m, 2H), 0.97 (t, J=7.2 Hz, 3H); Optical rotation:[α]_(D)−37.5 (c 1.04, methanol, 18° C.).

REFERENCE EXAMPLE 15(3)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.32 (butanol:acetic acid:water=4:2:1); NMR (CD₃OD): δ 4.16 (d,J=2.0 Hz, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.52 (m, 1H), 3.37 (m, 1H),3.28 (m, 1H), 3.22-3.13 (m, 2H), 2.46-1.93 (m, 6H), 1.80-1.64 (m, 5H),1.48-1.15 (m, 6H), 1.02-0.87 (m, 5H); Optical rotation: [α]_(D)+1.22 (c1.04, methanol, 26° C.).

REFERENCE EXAMPLE 15(4)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.05 (chloroform:methanol=10:1); NMR (CD₃OD): δ 4.13 (d, J=2.0Hz, 1H), 4.01-3.91 (m, 3H), 3.70 (m, 1H), 3.59-3.32 (m, 6H), 3.20 (m,1H), 2.47-2.19 (m, 3H), 2.11-1.69 (m, 5H), 1.47-1.17 (m, 5H), 0.70 (t,J=7.0 Hz, 3H).

REFERENCE EXAMPLE 15(5)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.04 (chloroform:methanol=10:1); NMR (CD₃OD): δ 4.00 (d, J=2.0Hz, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.53 (m, 1H), 3.40-3.34 (m, 3H),3.21 (m, 1H), 2.46-2.19 (m, 4H), 2.08 (m, 1H), 1.92-1.83 (m, 2H),1.70-1.50 (m, 6H), 1.45-1.26 (m, 5H), 0.97 (t, J=7.0 Hz, 3H).

REFERENCE EXAMPLE 15(6)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.15 (chloroform:methanol:acetic acid=20:4:1); NMR (CD₃OD): δ4.15 (d, J=2.1 Hz, 1H), 3.96 (m, 1H), 3.71 (m, 1H), 3.56-3.25 (m, 3H),3.20 (dd, J=9.6, 2.1 Hz, 1H), 3.13 (m, 1H), 2.51-1.95 (m, 5H), 1.75 (m,1H), 1.49 (m, 1H), 0.99 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.95(t, J=7.5 Hz, 3H).

REFERENCE EXAMPLE 15(7)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.16 (chloroform:methanol:acetic acid=20:4:1); NMR (CD₃OD): δ4.16 (d, J=2.1 Hz, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.47 (m, 1H),3.41-3.24 (m, 4H), 3.12 (m, 1H), 2.44 (m, 1H), 2.33 (m, 1H), 2.19 (m,1H), 2.08 (m, 1H), 2.03-1.89 (m, 2H), 1.84-1.62 (m, 4H), 1.50 (m, 1H),1.40-1.10 (m, 3H), 1.05-0.80 (m, 2H), 0.95 (t, J=7.5 Hz, 3H); Opticalrotation: [α]_(D)−2.92 (c 1.06, methanol, 25° C.).

REFERENCE EXAMPLE 15(8)(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.16 (chloroform:methanol:acetic acid=20:4:1); NMR (CD₃OD): δ4.15 (d, J=2.1 Hz, 1H), 3.95 (m, 1H), 3.71 (m, 1H), 3.52 (m, 1H),3.42-3.31 (m, 2H), 3.21 (m, 1H), 3.21 (dd, J=9.6, 2.1 Hz, 1H), 2.48-2.32(m, 2H), 2.23 (m, 1H), 2.14-1.96 (m, 2H), 1.72 (m, 1H), 1.55-1.33 (m,3H), 1.02-0.92 (m, 9H); Optical rotation: [α]_(D)−13.8 (c 1.00,methanol, 28° C.).

REFERENCE EXAMPLE 15(9)(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.17 (chloroform:methanol:acetic acid=20:4:1); NMR (CD₃OD): δ4.16 (d, J=2.1 Hz, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.52 (m, 1H),3.42-3.25 (m, 3H), 3.17 (m, 1H), 2.49-2.38 (m, 2H), 2.21 (m, 1H),2.14-1.90 (m, 3H), 1.84-1.61 (m, 5H), 1.55-1.13 (m, 6H), 1.04-0.81 (m,2H), 0.97 (t, J=7.2 Hz, 3H); Optical rotation:[α]_(D)−1.29 (c 1.09,methanol, 26° C.).

EXAMPLE 68(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-phenyloxypyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

To a solution of the compound prepared in Reference example 15 (120 mg)in dimethylformamide (1 ml) was added acetic acid (59 μl). The reactionmixture was added sodium triacetoxyborohydride (146 mg) and3-formyl-6-phenyloxypyridine (89 mg). The reaction mixture was stirredovernight at room temperature. The reaction mixture was added methanoland concentrated. The obtained residue was purified by columnchromatography on silica gel (ethyl acetate→chloroform:methanol=25:1)and the obtained compound was conversed to hydrochloride salt by using aconventional method to give the title compound (118 mg) having thefollowing physical data.

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD): δ 8.35 (d, J=2.1Hz, 1H), 8.12 (dd, J=8.7, 2.1 Hz, 1H), 7.49-7.40 (m, 2H), 7.27 (t, J=7.8Hz, 1H), 7.15 (d, J=7.8 Hz, 2H), 7.06 (d, J=8.7, 1H), 4.39 (s, 2H), 4.14(d, J=2.1 Hz, 1H), 4.07-3.93 (m, 1H), 3.82-3.67 (m, 1H), 3.58-3.40 (m,3H), 3.30-3.15 (m, 1H), 3.19 (dd, J=9.6, 2.1 Hz, 1H), 2.60-2.28 (m, 3H),2.18-2.05 (m, 1H), 2.05-1.90 (m, 1H), 1.80-1.55 (m, 1H), 1.50-1.25 (m,3H), 0.99 (d, J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz,3H); Optical rotation: [α]_(D)+10.80 (c 1.05, methanol, 24° C.); HPLCconditions column: CHIRALCEL OJ-R, 0.46×15 cm, DAICEL, OJR0CD-JB026:flow rate: 0.7 ml/min; solvent A solution: 0.1M aqueous solution ofpotassium dihydrogen phosphate, B solution: acetonitrile (A:B=76:24);UV: 225 nm; retention time: 11.53 min.

EXAMPLE 68(1) TO 68(59)

By the same procedure as described in Example 68 using the correspondingaldehyde derivatives instead of 3-formyl-6-phenyloxypyridine, thefollowing compounds were obtained.

EXAMPLE 68(1)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 7.45 (d,J=8.7 Hz, 2H), 7.00-6.96 (m, 6H), 4.27 (s, 2H), 4.14 (d, J=2.1 Hz, 1H),3.94-3.69 (m, 2H), 3.79 (s, 3H), 3.60-3.05 (m, 5H), 2.50-1.95 (m, 5H),1.70 (m, 1H), 1.50-1.30 (m, 3H), 1.00-0.93 (m, 9H).

EXAMPLE 68(2)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(3-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 7.51 (d,J=8.4 Hz, 2H), 7.28 (t, J=8.4 Hz, 1H), 7.08 (d, J=9.0 Hz, 2H), 6.75 (m,1H), 6.61-6.57 (m, 2H), 4.32 (s, 2H), 4.14 (d J=2.1 Hz, 1H), 3.99-3.73(m, 2H), 3.77 (s, 3H), 3.60-3.10 (m, 5H), 2.55-1.95 (m, 5H), 1.70 (m,1H), 1.50-1.30 (m, 3H), 1.00-0.93 (m, 9H).

EXAMPLE 68(3)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-fluorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 7.50 (d,J=8.7 Hz, 2H), 7.17-7.03 (m, 6H), 4.30 (s, 2H), 4.14 (d, J=2.1 Hz, 1H),3.97-3.71 (m, 2H), 3.60-3.10 (m, 5H), 2.55-1.95 (m, 5H), 1.70 (m, 1H),1.50-1.30 (m, 3H), 1.00-0.93 (m, 9H).

EXAMPLE 68(4)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-chlorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.31 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 7.53 (d,J=8.7 Hz, 2H), 7.38 (d, J=9.3 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 7.02 (d,J=9.3 Hz, 2H), 4.32 (s, 2H), 4.14 (d, J=1.8 Hz, 1H), 3.98-3.72 (m, 2H),3.60-3.10 (m, 5H), 2.55-2.00 (m, 5H), 1.70 (m, 1H), 1.50-1.30 (m, 3H),1.00-0.93 (m, 9H).

EXAMPLE 68(5)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(phenylcarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.87 (d, J=8.4Hz, 2H), 7.83-7.72 (m, 4H), 7.67 (m, 1H), 7.59-7.48 (m, 2H), 4.48 (s,2H), 4.14 (d, J=2.1 Hz, 1H), 4.05 (m, 1H), 3.80 (m, 1H), 3.59-3.37 (m,3H), 3.20 (m, 1H), 3.19 (dd, J=9.6, 2.1 Hz, 1H), 2.60-2.28 (m, 3H), 2.14(m, 1H), 2.00 (m, 1H), 1.70 (m, 1H), 1.52-1.23 (m, 3H), 0.99 (d, J=6.6Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 68(6)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(1-phenyl-1-hydroxymethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.32 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.62-7.40 (m,4H), 7.40-7.18 (m, 5H), 5.81 (s, 1H), 4.32 (s, 2H), 4.13 (d, J=2.1 Hz,1H), 3.99 (m, 1H), 3.73 (m, 1H), 3.55-3.38 (m, 3H), 3.13 (m, 1H), 3.19(dd, J=9.6, 2.1 Hz, 1H), 2.52-2.33 (m, 2H), 2.24 (m, 1H), 2.09 (m, 1H),1.98 (m, 1H), 1.67 (m, 1H), 1.50-1.25 (m, 3H), 0.98 (d, J=6.6 Hz, 3H),0.96 (d, J=6.6 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 68(7)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(morpholin-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.59 (d, J=8.7Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.7Hz, 2H), 4.35 (s, 2H), 4.14 (d, J=1.8 Hz, 1H), 3.99 (m, 1H), 3.85-3.35(m, 12H), 3.23 (m, 1H), 3.19 (dd, J=9.3, 1.8 Hz, 1H), 2.55-2.41 (m, 2H),2.32 (m, 1H), 2.12 (m, 1H), 2.01 (m, 1H), 1.68 (m, 1H), 1.50-1.25 (m,3H), 0.99 (d, J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz,3H).

EXAMPLE 68(8)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.19 (ethyl acetate:methanol=10:1); NMR (CD₃OD): δ 8.58 (d,J=2.7, 0.6 Hz, 1H), 8.17 (dd, J=9.0, 2.7 Hz, 1H), 7.89 (d, J=9.0 Hz,1H), 7.74 (d, J=9.0 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H), 4.40 (s, 2H), 4.15(d, J=2.1 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.60-3.42 (m, 3H),3.30-3.16 (m, 2H), 2.76 (s, 3H), 2.64-2.32 (m, 3H), 2.18-1.94 (m, 2H),1.70 (m, 1H), 1.48-1.26 (m, 3H), 1.00 (d, J=6.3 Hz, 3H), 0.98 (d, J=6.3Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 68(9)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(pyridin-1-oxido-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=5:1); NMR (CD₃OD): δ 8.56 (m, 1H),8.45 (m, 1H), 7.81-7.68 (m, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4Hz, 2H), 4.41 (s, 2H), 4.15 (d, J=1.8 Hz, 1H), 4.00 (m, 1H), 3.78 (m,1H), 3.58-3.42 (m, 3H), 3.28-3.16 (m, 2H), 2.64-2.26 (m, 3H), 2.20-1.92(m, 2H), 1.68 (m, 1H), 1.52-1.28 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98(d, J=6.6 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 68(10)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxypiperidin-1-ylmethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.69 (chloroform:methanol:28% aqueous solution ofammonia=100:10:1); NMR (CD₃OD): δ 7.75 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4Hz, 2H), 4.41 (s, 2H), 4.38 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.14-3.94(m, 2H), 3.78 (m, 1H), 3.58-3.40 (m, 4H), 3.30-3.00 (m, 4H), 2.68-2.36(m, 3H), 2.20-1.58 (m, 8H), 1.50-1.26 (m, 3H), 0.99 (d, J=6.6 Hz, 3H),0.98 (d, J=6.6 Hz, 3H), 0.95 (t, J=6, 9 Hz, 3H).

EXAMPLE 68(11)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.65 (chloroform:methanol=5:1); NMR (CD₃OD): δ 4.32 (m, 1H),4.27 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.76 (m, 1H),3.60-3.42 (m, 3H), 3.36-3.16 (m, 2H), 2.64-2.42 (m, 3H), 2.49 (s, 3H),2.44 (s, 3H), 2.18-1.22 (m, 16H), 1.00 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.6Hz, 3H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 68(12)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(1,3,5-trimethylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=5:1); NMR (CD₃OD): δ 4.27 (s, 2H),4.15 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.85 (s, 3H), 3.76 (m, 1H),3.60-3.44 (m, 3H), 3.28-3.16 (m, 2H), 2.64-2.32 (m, 3H), 2.44 (s, 3H),2.40 (s, 3H), 2.18-1.92 (m, 2H), 1.70 (m, 1H), 1.48-1.26 (m, 3H), 1.00(d, J=6.6 Hz, 3H) 0.99 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 68(13)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-aminosulfonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=5:1); NMR (CD₃OD): δ 7.91 (d, J=8.7Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7Hz, 2H), 4.35 (s, 2H), 4.15 (d, J=2.4 Hz, 1H), 3.98 (m, 1H), 3.72 (m,1H), 3.58-3.38 (m, 3H), 3.28-3.18 (m, 2H), 2.56-1.92 (m, 5H), 1.70 (m,1H), 1.54-1.28 (m, 3H), 1.00 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H),0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 68(14)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylthiophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.53 (d, J=9.0Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.0Hz, 2H), 4.33 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 3.98 (m, 1H), 3.72 (m,1H), 3.58-3.40 (m, 3H), 3.28-3.10 (m, 2H), 2.52-1.92 (m, 5H), 2.47 (s,3H), 1.70 (m, 1H), 1.50-1.28 (m, 3H), 1.02-0.86 (m, 9H).

EXAMPLE 68(15)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.95 (d, J=9.0Hz, 2H), 7.63 (d, J=8.1 Hz, 2H), 7.24-7.18 (m, 4H), 4.39 (s, 2H), 4.14(d, J=2.4 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.60-3.46 (m, 3H),3.28-3.10 (m, 2H), 3.12 (s, 3H), 2.54-1.94 (m, 5H), 1.70 (m, 1H),1.50-1.30 (m, 3H), 1.02-0.86 (m, 9H).

EXAMPLE 68(16)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-cyanophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.73 (d, J=8.7Hz, 2H), 7.64 (d, J=9.0 Hz, 2H), 7.21 (d, J=9.0 Hz, 2H), 7.14 (d, J=8.7Hz, 2H), 4.38 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.02 (m, 1H), 3.76 (m,1H), 3.60-3.40 (m, 3H), 3.28-3.14 (m, 2H), 2.54-2.26 (m, 3H), 2.20-1.90(m, 2H), 1.66 (m, 1H), 1.50-1.28 (m, 3H), 1.02-0.84 (m, 9H).

EXAMPLE 68(17)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(phenylthio)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD): δ 7.50-7.34 (m,7H), 7.30 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.13 (d, J=2.1 Hz, 1H), 3.98(m, 1H), 3.72 (m, 1H), 3.56-3.36 (m, 3H), 3.24-3.08 (m, 2H), 2.50-2.18(m, 3H), 2.18-1.94 (m, 2H), 1.68 (m, 1H), 1.50-1.28 (m, 3H), 1.10-0.88(m, 9H).

EXAMPLE 68(18)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.70 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.31 (d, J=8.7 Hz,2H), 6.94 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.04(m, 1H), 3.80 (m, 1H), 3.64-3.48 (m, 3H), 3.38-3.18 (m, 2H), 2.70-2.30(m, 3H), 2.44 (s, 3H), 2.36 (s, 3H), 2.20-1.94 (m, 2H), 1.68 (m, 1H),1.50-1.26 (m, 3H), 1.02-0.84 (m, 9H).

EXAMPLE 68(19)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylsulfonylaminophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.72 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.47 (d, J=9.0Hz, 2H), 7.41 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 4.15 (d, J=1.8 Hz, 1H),4.02 (m, 1H), 3.78 (m, 1H), 3.62-3.48 (m, 3H), 3.38-3.18 (m, 2H), 3.04(s, 3H), 2.68-2.36 (m, 3H), 2.41 (s, 3H), 2.39 (s, 3H), 2.20-1.96 (m,2H), 1.68 (m, 1H), 1.50-1.30 (m, 3H), 1.02-0.88 (m, 9H).

EXAMPLE 68(20)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.12 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.07 (d, J=9.0 Hz,2H), 7.78 (d, J=9.0 Hz, 2H), 4.30 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.02(m, 1H), 3.76 (m, 1H), 3.62-3.48 (m, 3H), 3.40-3.18 (m, 6H), 2.95 (s,6H), 2.64 (m, 1H), 2.49 (s, 3H), 2.42-2.36 (m, 2H), 2.41 (s, 3H),2.18-1.96 (m, 2H), 1.68 (m, 1H), 1.50-1.32 (m, 3H), 1.08-0.90 (m, 9H).

EXAMPLE 68(21)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.15 (d, J=1.8 Hz, 1H),4.04 (m, 1H), 3.78 (m, 1H), 3.62-3.48 (m, 3H), 3.40-3.18 (m, 6H), 2.66(m, 1H), 2.54-2.38 (m, 2H), 2.49 (s, 3H), 2.42 (s, 3H), 2.20-1.94 (m,2H), 1.82-1.62 (m, 5H), 1.50-1.30 (m, 3H), 1.02-0.88 (m, 9H).

EXAMPLE 68(22)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(6-methylpyridin-1-oxido-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.26 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.58 (m, 1H),7.81-7.71 (m, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 4.40(s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.78 (m, 1H), 3.62-3.40(m, 3H), 3.30-3.16 (m, 2H), 2.66-2.38 (m, 3H), 2.66 (s, 3H), 2.18-1.94(m, 2H), 1.70 (m, 1H), 1.50-1.28 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98(d, J=6.6 Hz, 3H), 0.96 (t, J=6.9 Hz, 3H).

EXAMPLE 68(23)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.46 (d, J=8.7Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0Hz, 2H), 4.30 (s, 2H), 4.13 (d, J=2.0 Hz, 1H), 3.98 (m, 1H), 3.72 (m,1H), 3.53-3.42 (m, 3H), 3.23-3.11 (m, 2H), 2.50-1.97 (m, 6H), 1.70 (m,1H), 1.39-1.30 (m, 3H), 0.98 (d, J=6.5 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H),0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 68(24)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-(4-methoxyphenyloxy)pyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.41 (m, 1H),8.18 (m, 1H), 7.13-6.99 (m, 5H), 4.40 (s, 2H), 4.13 (d, J=2.0 Hz, 1H),4.00 (m, 1H), 3.82 (s, 3H), 3.75 (m, 1H), 3.53-3.45 (m, 3H), 3.24 (m,1H), 3.19 (dd, J=9.5, 2.0 Hz, 1H), 2.59-2.39 (m, 3H), 2.15-1.95 (m, 2H),1.70 (m, 1H), 1.40-1.31 (m, 3H), 0.98 (d, J=6.5 Hz, 3H), 0.97 (d, J=6.5Hz, 3H), 0.94 (t, J=7.5 Hz, 3H).

EXAMPLE 68(25)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(methylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.29 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 8.00 (d, J=9.0Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 4.32 (s, 2H), 4.16 (d, J=2.0 Hz, 1H),4.05 (m, 1H), 3.79 (m, 1H), 3.64-3.50 (m, 3H), 3.29-3.19 (m, 2H),2.59-2.35 (m, 3H), 2.58 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H), 2.15 (m,1H), 2.02 (m, 1H), 1.72 (m, 1H), 1.41-1.35 (m, 3H), 0.99 (d, J=6.5 Hz,3H), 0.98 (d, J=6.5 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 68(26)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.21 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.98 (d, J=8.5Hz, 2H), 7.75 (d, J=8.5 Hz, 2H), 4.31 (s, 2H), 4.15 (d, J=2.0 Hz, 1H),4.04 (m, 1H), 3.79 (m, 1H), 3.69 (t, J=6.0 Hz, 2H), 3.61-3.51 (m, 3H),3.23-3.17 (m, 4H), 2.87 (s, 3H), 2.58-2.44 (m, 3H), 2.48 (s, 3H), 2.40(s, 3H), 2.15 (m, 1H), 2.02 (m, 1H), 1.71 (m, 1H), 1.41-1.35 (m, 3H),0.99 (d, J=6.5 Hz, 3H), 0.98 (d, J=6.5 Hz, 3H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 68(27)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.20 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 8.03 (d, J=8.7Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.15 (d, J=2.0 Hz, 1H),4.04 (m, 1H), 3.79 (m, 1H), 3.63-3.51 (m, 3H), 3.56 (t, J=6.0 Hz, 2H),3.34-3.29 (m, 1H), 3.20 (dd, J=9.5, 2.0 Hz, 1H), 3.01 (t, J=6.0 Hz, 2H),2.59-2.43 (m, 3H), 2.47 (s, 3H), 2.40 (s, 3H), 2.15 (m, 1H), 2.02 (m,1H), 1.71 (m, 1H), 1.41-1.35 (m, 3H), 0.99 (d, J=6.5 Hz, 3H), 0.98 (d,J=6.5 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 68(28)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.35 (ethyl acetate:methanol=2:1); NMR (CD₃OD):δ 7.62 (d, J=9.0Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 4.32 (s, 2H), 4.16 (d, J=2.0 Hz, 1H),4.05 (m, 1H), 3.79 (m, 1H), 3.61-3.49 (m, 3H), 3.34-3.29 (m, 1H), 3.20(dd, J=9.5, 2.0 Hz, 1H), 3.13 (s, 3H), 3.04 (s, 3H), 2.55-2.34 (m, 3H),2.42 (s, 3H), 2.39 (s, 3H), 2.18 (m, 1H), 2.02 (m, 1H), 1.73 (m, 1H),1.41-1.34 (m, 3H), 0.99 (d, J=6.5 Hz, 3H), 0.98 (d, J=6.5 Hz, 3H), 0.96(t, J=7.0 Hz, 3H).

EXAMPLE 68(29)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(morpholin-4-yl)ethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.33 (ethyl acetate:methanol=2:1); NMR (CD₃OD):δ 8.06 (d, J=8.7Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.15 (d, J=2.0 Hz, 1H),4.10-4.01 (m, 3H), 3.88-3.76 (m, 3H), 3.61-3.53 (m, 5H), 3.37-3.19 (m,8H), 2.59-2.37 (m, 3H), 2.48 (s, 3H), 2.40 (s, 3H), 2.15 (m, 1H), 2.02(m, 1H), 1.71 (m, 1H), 1.40-1.35 (m, 3H), 0.99 (d, J=6.5 Hz, 3H), 0.98(d, J=6.5 Hz, 3H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 68(30)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.72 (d, J=8.7Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.15 (d, J=2.1 Hz, 1H),4.05 (m, 1H), 3.79 (m, 1H), 3.66-3.46 (m, 7H), 3.25 (m, 1H), 3.21 (dd,J=9.6, 2.1 Hz, 1H), 2.65-2.35 (m, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.16(m, 1H), 2.09-1.87 (m, 5H), 1.70 (m, 1H), 1.53-1.30 (m, 3H), 1.00 (d,J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 68(31)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfinylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.74 (d, J=8.7Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7Hz, 2H), 4.37 (s, 2H), 4.14 (d, J=2.4 Hz, 1H), 4.02 (m, 1H), 3.76 (m,1H), 3.58-3.42 (m, 3H), 3.25-3.14 (m, 2H), 2.80 (s, 3H), 2.55-2.38 (m,2H), 2.29 (m, 1H), 2.15 (m, 1H), 2.01 (m, 1H), 1.70 (m, 1H), 1.50-1.27(m, 3H), 1.04-0.90 (m, 9H).

EXAMPLE 68(32)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.31 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.96 (d, J=8.7Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.15 (d, J=2.4 Hz, 1H),4.06 (m, 1H), 3.79 (m, 1H), 3.64-3.46 (m, 3H), 3.29-3.14 (m, 2H), 2.73(s, 6H), 2.59-2.44 (m, 2H), 2.47 (s, 3H), 2.39 (s, 3H), 2.35 (m, 1H),2.17 (m, 1H), 2.02 (m, 1H), 1.71 (m, 1H), 1.51-1.26 (m, 3H), 1.05-0.89(m, 9H).

EXAMPLE 68(33)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholin-4-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.95 (d, J=8.7Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.15 (d, J=2.1 Hz, 1H),4.06 (m, 1H), 3.80 (m, 1H), 3.74-3.68 (m, 4H), 3.64-3.48 (m, 3H),3.28-3.14 (m, 2H), 3.05-2.98 (m, 4H), 2.59-2.44 (m, 2H), 2.47 (s, 3H),2.39 (s, 3H), 2.35 (m, 1H), 2.17 (m, 1H), 2.02 (m, 1H), 1.71 (m, 1H),1.52-1.30 (m, 3H), 1.05-0.90 (m, 9H).

EXAMPLE 68(34)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-aminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.22 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.92 (d, J=8.7Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7Hz, 2H), 4.37 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.78 (m,1H), 3.60-3.38 (m, 3H), 3.28-3.10 (m, 2H), 2.60-2.26 (m, 3H), 2.20-1.88(m, 2H), 1.68 (m, 1H), 1.54-1.22 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98(d, J=6.6 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 68(35)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.24 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.85 (d, J=8.7Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.7Hz, 2H), 4.37 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.76 (m,1H), 3.56-3.42 (m, 3H), 3.26-3.18 (m, 2H), 2.92 (s, 3H), 2.60-2.28 (m,3H), 2.18-1.94 (m, 2H), 1.70 (m, 1H), 1.50-1.30 (m, 3H), 1.00 (d, J=6.6Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 68(36)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.41 (s, 4H),4.34 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.04 (m, 1H), 3.79 (m, 1H),3.65-3.50 (m, 3H), 3.34 (m, 1H), 3.21 (dd, J=9.6, 2.1 Hz, 1H), 2.66 (m,1H), 2.55-2.42 (m, 2H), 2.47 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H), 2.14(m, 1H), 2.01 (m, 1H), 1.69 (m, 1H), 1.52-1.30 (m, 3H), 1.00 (d, J=6.6Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 68(37)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane

TLC: Rf 0.35 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.99 (d, J=8.7 Hz,2H), 7.72 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.06(m, 1H), 3.80 (m, 1H), 3.63-3.48 (m, 3H), 3.32-3.17 (m, 2H), 3.29 (q,J=7.2 Hz, 4H), 2.54-2.13 (m, 4H), 2.45 (s, 3H), 2.39 (s, 3H), 2.02 (m,1H), 1.72 (m, 1H), 1.52-1.33 (m, 3H), 1.15 (t, J=7.2 Hz, 6H), 1.00 (d,J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.96 (t, J=6.9 Hz, 3H).

EXAMPLE 68(38)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.22 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.82 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.15 (d, J=1.8 Hz, 1H),4.11-3.94 (m, 3H), 3.80 (m, 1H), 3.65-3.48 (m, 5H), 3.34-3.18 (m, 4H),2.91 (s, 3H), 2.86-2.70 (m, 2H), 2.68-2.36 (m, 3H), 2.49 (s, 3H), 2.40(s, 3H), 2.15 (m, 1H), 2.02 (m, 1H), 1.70 (m, 1H), 1.50-1.27 (m, 3H),1.05-0.90 (m, 9H).

EXAMPLE 68(39)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(5-chloro-3-methyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.63-7.48 (m,5H), 4.33 (s, 2H), 4.14 (d, J=1.8 Hz, 1H), 4.10 (m, 1H), 3.83 (m, 1H),3.66-3.45 (m, 3H), 3.29-3.16 (m, 2H), 2.62-2.32 (m, 3H), 2.44 (s, 3H),2.17 (m, 1H), 2.01 (m, 1H), 1.71 (m, 1H), 1.52-1.11 (m, 3H), 1.05-0.88(m, 9H).

EXAMPLE 68(40)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholin-4-ylcarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.66-7.57 (m,4H), 4.31 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.05 (m, 1H), 3.88-3.39 (m,12H), 3.25 (m, 1H), 3.20 (dd, J=9.6, 2.1 Hz, 1H), 2.65-2.27 (m, 3H),2.43 (s, 3H), 2.40 (s, 3H), 2.17 (m, 1H), 2.02 (m, 1H), 1.71 (m, 1H),1.54-1.27 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.96(t, J=7.2 Hz, 3H).

EXAMPLE 68(41)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.42 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.03 (d, J=8.7 Hz,2H), 7.61 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.16 (d, J=1.8 Hz, 1H), 4.04(m, 1H), 3.80 (m, 1H), 3.74 (t, J=5.7 Hz, 2H), 3.64-3.48 (m, 3H), 3.54(t, J=5.7 Hz, 2H), 3.30-3.16 (m, 2H), 2.64-2.34 (m, 3H), 2.45 (s, 3H),2.41 (s, 3H), 2.22-1.92 (m, 2H), 1.72 (m, 1H), 1.52-1.26 (m, 3H), 1.01(d, J=6.6 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 68(42)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(2-(N,N-dimethylamino)ethylaminocarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.19 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.93 (d, J=9.0 Hz,2H), 7.61 (d, J=8.4 Hz, 2H), 7.18-7.08 (m, 4H), 4.36 (s, 2H), 4.14 (d,J=1.8 Hz, 1H), 4.00 (m, 1H), 3.80-3.70 (m, 3H), 3.54-3.42 (m, 3H), 3.38(t, J=6.3 Hz, 2H), 3.26-3.18 (m, 2H), 2.98 (s, 6H), 2.60-2.30 (m, 3H),2.18-1.96 (m, 2H), 1.68 (m, 1H), 1.50-1.30 (m, 3H), 1.00-0.90 (m, 9H).

EXAMPLE 68(43)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(pyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.31 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.74 (m, 1H),8.62 (d, J=5.4 Hz, 1H), 8.24 (m, 1H), 8.14 (m, 1H), 7.76 (d, J=8.4 Hz,2H), 7.34 (d, J=8.4 Hz, 2H), 4.40 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.00(m, 1H), 3.76 (m, 1H), 3.60-3.44 (m, 3H), 3.30-3.16 (m, 2H), 2.60 (m,1H), 2.50-2.40 (m, 2H), 2.26-1.86 (m, 2H), 1.66 (m, 1H), 1.50-1.30 (m,3H), 1.02-0.88 (m, 9H).

EXAMPLE 68(44)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.42 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.04 (d, J=8.7 Hz,2H), 7.59 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.7 Hz,2H), 4.37 (s, 2H), 4.15 (d, J=2.4 Hz, 1H), 4.02 (m, 1H), 3.76 (m, 1H),3.60-3.44 (m, 3H), 3.24-3.08 (m, 2H), 2.56-1.92 (m, 5H), 1.70 (m, 1H),1.50-1.26 (m, 3H), 1.08-0.90 (m, 9H).

EXAMPLE 68(45)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.49 (d, J=9.0Hz, 2H), 7.20 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 6.92 (d, J=9.0Hz, 2H), 4.32 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 3.98 (m, 1H), 3.72 (m,1H), 3.58-3.36 (m, 3H), 3.26-3.08 (m, 2H), 2.52-1.82 (m, 5H), 2.33 (s,3H), 1.68 (m, 1H), 1.50-1.28 (m, 3H), 1.02-0.86 (m, 9H).

EXAMPLE 68(46)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(2,4-difluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.63 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.56 (m, 1H),7.33-7.16 (m, 2H), 4.32 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.06 (m, 1H),3.80 (m, 1H), 3.62-3.44 (m, 3H), 3.28-3.16 (m, 2H), 2.62-1.84 (m, 5H),2.39 (s, 3H), 2.28 (s, 3H), 1.72 (m, 1H), 1.54-1.28 (m, 3H), 1.01 (d,J=6.6 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

EXAMPLE 68(47)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(pyridin-2-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.52 (m, 1H),8.01 (m, 1H), 7.81 (m, 1H), 7.41 (m, 1H), 4.33 (s, 2H), 4.16 (d, J=1.8Hz, 1H), 4.06 (m, 1H), 3.80 (m, 1H), 3.64-3.46 (m, 3H), 3.26-3.12 (m,2H), 2.68 (s, 3H), 2.58-2.24 (m, 3H), 2.41 (s, 3H), 2.18 (m, 1H), 2.04(m, 1H), 1.70 (m, 1H), 1.54-1.26 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.99(d, J=6.6 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 68(48)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylaminocarbonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.18 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.99 (d, J=8.7Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.15 (d, J=2.1 Hz, 1H),4.04 (m, 1H), 3.79 (m, 1H), 3.64-3.49 (m, 3H), 3.30-3.17 (m, 2H), 2.94(s, 3H), 2.59 (m, 1H), 2.51-2.36 (m, 2H), 2.44 (s, 3H), 2.41. (s, 3H),2.15 (m, 1H), 2.02 (m, 1H), 1.70 (m, 1H), 1.52-1.27 (m, 3H), 1.05-0.91(m, 9H).

EXAMPLE 68(49)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-cyclohexyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.44 (d, J=8.7Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 4.38 (m, 1H), 4.27 (s, 2H), 4.14 (d,J=2.1 Hz, 1H), 3.96 (m, 1H), 3.70 (m, 1H), 3.58-3.36 (m, 3H), 3.26-3.08(m, 2H), 2.54-1.26 (m, 19H), 0.99 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz,3H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 68(50)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(3,4,5,6-tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.47 (d, J=8.7Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 4.64 (m, 1H), 4.29 (s, 2H), 4.14 (d,J=2.4 Hz, 1H), 4.04-3.86 (m, 3H), 3.80-3.36 (m, 6H), 3.26-3.08 (m, 2H),2.52-1.90 (m, 7H), 1.80-1.58 (m, 3H), 1.50-1.26 (m, 3H), 0.99 (d, J=6.6Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 68(51)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenylmethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.37 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.96 (d, J=8.4Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4Hz, 2H), 4.52 (s, 2H), 4.43 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.04 (m,1H), 3.77 (s, 3H), 3.77 (m, 1H), 3.58-3.40 (m, 3H), 3.26-3.10 (m, 2H),2.54-2.22 (m, 3H), 2.20-1.90 (m, 2H), 1.66 (m, 1H), 1.50-1.26 (m, 3H),0.99 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 68(52)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(cyclohexylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.91 (d, J=8.3Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 4.42 (s, 2H), 4.13 (d, J=2.0 Hz, 1H),4.03 (m 1H), 3.90-3.72 (m, 2H), 3.56-3.43 (m, 3H), 3.25 (m, 1H), 3.18(dd, J=9.6, 2.0 Hz, 1H), 2.53-2.40 (m, 2H), 2.30 (m, 1H), 2.14 (m, 1H),2.06-1.67 (m, 8H), 1.50-1.33 (m, 7H), 0.98 (d, J=6.6 Hz, 3H), 0.96 (d,J=6.6 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H).

EXAMPLE 68(53)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.34 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.61-7.57 (m,4H), 7.14 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 4.36 (s, 2H), 4.14(d, J=2.0 Hz, 1H), 4.00 (m, 1H), 3.74 (m, 1H), 3.62-3.45 (m, 7H),3.24(m, 1H), 3.19 (dd, J=9.6, 2.0 Hz, 1H), 2.56-2.29 (m, 3H), 2.15-1.89(m, 6H), 1.70 (m, 1H), 1.40-1.33 (m, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 68(54)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-fluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.37 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.56-7.51 (m,2H), 7.35-7.28 (m, 2H), 4.31 (s, 2H), 4.15 (d, J=2.0 Hz, 1H), 4.03 (m,1H), 3.78 (m, 1H), 3.61-3.49 (m, 3H), 3.34 (m, 1H), 3.20 (dd, J=9.6, 2.0Hz, 1H), 2.68-2.42 (m, 6H), 2.38 (s, 3H), 2.17 (m, 1H), 2.02 (m, 1H),1.70 (m, 1H), 1.50-1.35 (m, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 68(55)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-phenylethyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.13 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.32-7.20 (m,3H), 7.11-7.08 (m, 2H), 4.45 (t, J=6.6 Hz, 2H), 4.20 (s, 2H), 4.16 (d,J=1.8 Hz, 1H), 3.90 (m, 1H), 3.70-3.48 (m, 3H), 3.42-3.30 (m, 2H), 3.21(m, 1H), 3.14 (t, J=6.6 Hz, 2H), 2.76-2.38 (m, 3H), 2.50 (s, 3H),2.20-1.88 (m, 2H), 1.97 (s, 3H), 1.74 (m, 1H), 1.56-1.34 (m, 3H), 1.01(d, J=6.6 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.97 (t, J=6.9 Hz, 3H).

EXAMPLE 68(56)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.13 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.44-7.24 (m,5H), 5.16 (s, 2H), 4.54 (m, 1H), 4.40-4.20 (m, 2H), 4.25 (s, 2H), 4.15(d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.82-3.42 (m, 5H), 3.30-2.88 (m, 3H),2.64-2.30 (m, 3H), 2.47 (s, 3H), 2.37 (s, 3H), 2.20-1.84 (m, 6H), 1.70(m, 1H), 1.52-1.26 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz,3H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 68(57)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(2-hydroxyethylaminocarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.47 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.89 (d, J=9.0 Hz,2H), 7.61 (d, J=9.0 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz,2H), 4.37 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.78 (m, 1H),3.71 (t, J=5.7 Hz, 2H), 3.60-3.40 (m, 3H), 3.51 (t, J=5.7 Hz, 2H),3.30-3.12 (m, 2H), 2.60-2.24 (m, 3H), 2.22-1.92 (m, 2H), 1.70 (m, 1H),1.56-1.24 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.96(t, J=7.5 Hz, 3H).

EXAMPLE 68(58)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylsulfonylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.41 (chloroform:methanol=5:1); NMR (CD₃OD):δ 4.44 (m, 1H), 4.25(s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.06-3.64 (m, 4H), 3.60-3.44 (m, 3H),3.28-3.16 (m, 2H), 3.06-2.92 (m, 2H), 2.90 (s, 3H), 2.64-1.90 (m, 9H),2.47 (s, 3H), 2.37 (s, 3H), 1.68 (m, 1H), 1.50-1.24 (m, 3H), 1.00 (d,J=6.6 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 68(59)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxymethylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane

TLC: Rf 0.32 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.36 (d, J=8.4Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 4H), 4.58 (s, 2H),4.12 (d, J=2.4 Hz, 1H), 3.73 (s, 2H), 3.47 (m, 1H), 3.30-2.90 (m, 6H),2.31-1.83 (m, 5H), 1.64 (m, 1H), 1.55-1.23 (m, 3H), 0.97 (d, J=6.6 Hz,6H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 69(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(6-phenyloxypyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure described in Example 68 using the compoundprepared in Reference example 15(8) instead of the compound prepared inReference example 3, the title compound (110 mg) having the followingphysical data was obtained.

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.35 (d, J=2.1Hz, 1H), 8.12 (dd, J=8.7, 2.1 Hz, 1H), 7.49-7.40 (m, 2H), 7.27 (t, J=7.8Hz, 1H), 7.15 (d, J=7.8 Hz, 2H), 7.06 (d, J=8.7, 1H), 4.39 (s, 2H), 4.14(d, J=2.1 Hz, 1H), 4.07-3.93 (m, 1H), 3.82-3.67 (m, 1H), 3.58-3.40 (m,3H), 3.30-3.15 (m, 1H), 3.19 (dd, J=9.6, 2.1 Hz, 1H), 2.60-2.28 (m, 3H),2.18-2.05 (m, 1H), 2.05-1.90 (m, 1H), 1.80-1.55 (m, 1H), 1.50-1.25 (m,3H), 0.99 (d, J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.2 Hz,3H); Optical rotation:[α]_(D)−10.1 (c 1.04, methanol, 25° C.); HPLCconditions column: CHIRALCEL OJ-R, 0.46×15 cm, DAICEL, OJR0CD-JB026;flow rate: 0.7 ml/min; solvent A solution: 0.1M aqueous solution ofpotassium dihydrogen phosphate, B solution: acetonitrile (A:B=76:24);UV: 225 nm; retention time: 8.65 min.

EXAMPLE 70(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure described in Example 68 using the compoundprepared in Reference example 15(1) instead of the compound prepared inReference example 15, and using[4-(4-formyl-3,5-dimethylpyrazolyl)phenyl]-N,N-dimethylcarboxamideinstead of 3-formyl-6-phenyloxypyridine, the title compound having thefollowing physical data was obtained.

TLC: Rf 0.62 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.65-7.52 (m, 4H),4.33 (s, 2H), 4.03 (dd, J=7.8, 4.5 Hz, 1H), 3.96-3.72 (m, 2H), 3.64-3.54(m, 2H), 3.50-3.36 (m, 2H), 3.14 (s, 3H), 3.05 (s, 3H), 2.60-2.42 (m,2H), 2.44 (s, 3H), 2.41 (s, 3H), 2.36-2.10 (m, 2H), 1.90-1.24 (m, 7H),0.97 (t, J=7.2 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 70(1) TO 70(43)

By the same procedure as described in Example 70 using the correspondingaldehyde derivatives respectively instead of[4-(4-formyl-3,5-dimethylpyrazolyl)phenyl]-N,N-dimethylcarboxamide, thefollowing compounds having the following physical data were obtained.

EXAMPLE 70(1)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.56 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.73 (d, J=8.7 Hz,2H), 7.60 (d, J=8.7 Hz, 2H), 4.33 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H),3.96-3.74 (m, 2H), 3.66-3.36 (m, 8H), 2.58-2.40 (m, 2H), 2.44 (s, 3H),2.41 (s, 3H), 2.34-2.12 (m, 2H), 2.06-1.26 (m, 11H), 0.97 (t, J=7.2 Hz,3H), 0.96 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 70(2)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholin-4-ylcarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.57 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.64 (d, J=9.0 Hz,2H), 7.60 (d, J=9.0 Hz, 2H), 4.33 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H),3.98-3.36 (m, 14H), 2.58-2.36 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H),2.32-2.14 (m, 2H), 1.90-1.24 (m, 7H), 0.97 (t, J=7.2 Hz, 3H), 0.96 (d,J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 70(3)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylsulfonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.09 (d, J=8.4Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 4.48 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz,1H), 3.92-3.70 (m, 2H), 3.56-3.36 (m, 4H), 3.16 (s, 3H), 2.48-2.30 (m,2H), 2.28-2.06 (m, 2H), 1.90-1.24 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95(d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 70(4)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.96 (d, J=8.7Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.7Hz, 2H), 4.40 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.94-3.72 (m, 2H),3.58-3.36 (m, 4H), 3.12 (s, 3H), 2.54-2.36 (m, 2H), 2.18-2.08 (m, 2H),1.88-1.26 (m, 7H), 0.96 (t, J=6.9 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94(d, J=6.3 Hz, 3H).

EXAMPLE 70(5)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(morpholin-4-yl)ethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.60 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.07 (d, J=8.4 Hz,2H), 7.78 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 4.16-3.98 (m, 3H), 3.94-3.76(m, 4H), 3.64-3.40 (m, 6H), 3.38-3.18 (m, 6H), 2.62-2.44 (m, 2H), 2.49(s, 3H), 2.41 (s, 3H), 2.36-2.12 (m, 2H), 1.90-1.24 (m, 7H), 0.97 (t,J=6.6 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 70(6)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.50 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.02 (d, J=9.0 Hz,2H), 7.83 (d, J=9.0 Hz, 2H), 4.32 (s, 2H), 4.03 (dd, J=7.8, 4.5 Hz, 1H),4.03-3.76 (m, 4H), 3.68-3.56 (m, 4H), 3.54-3.42 (m, 2H), 3.30-3.20 (m,2H), 2.92 (s, 3H), 2.86-2.72 (m, 2H), 2.64-2.48 (m, 2H), 2.51 (s, 3H),2.42 (s, 3H), 2.32-2.12 (m, 2H), 1.90-1.26 (m, 7H), 0.97 (t, J=6.6 Hz,3H), 0.96 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 70(7)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfinylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.75 (d, J=9.0Hz, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.23 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.0Hz, 2H), 4.38 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.92-3.72 (m, 2H),3.58-3.36 (m, 4H), 2.81 (s, 3H), 2.52-2.36 (m, 2H), 2.30-2.10 (m, 2H),1.90-1.26 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94(d, J=6.3 Hz, 3H).

EXAMPLE 70(8)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridin-1-oxido-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=5:1); NMR (CD₃OD): 8.66 (s, 1H),8.53-8.52 (m, 1H), 7.88-7.78 (m, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.34 (d,J=8.7 Hz, 2H), 4.41 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.92-3.70 (m,2H), 3.66-3.40 (m, 4H), 2.66-2.48 (m, 2H), 2.26-2.08 (m, 2H), 1.90-1.26(m, H), 0.96 (t, J=7.5 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6Hz, 3H).

EXAMPLE 70(9)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.53 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.03 (d, J=8.4 Hz,2H), 7.62 (d, J=8.4 Hz, 2H), 4.33 (s, 2H), 4.03 (dd, J=7.8, 4.5 Hz, 1H),3.98-3.76 (m, 2H), 3.74 (t, J=5.7 Hz, 2H), 3.68-3.58 (m, 2H), 3.54 (t,J=5.7 Hz, 2H), 3.54-3.40 (m, 2H), 2.64-2.48 (m, 2H), 2.46 (s, 3H), 2.43(s, 3H), 2.32-2.10 (m, 2H), 1.90-1.30 (m, 7H), 0.97 (t, J=6.6 Hz, 3H),0.96 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 70(10)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(morpholin-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.61 (d, J=8.7 Hz,2H), 7.49 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz,2H), 4.37 (s, 2H), 4.02 (dd, J=7.8, 4.8 Hz, 1H), 3.90-3.36 (m, 14H),2.58-2.38 (m, 2H), 2.28-2.08 (m, 2H), 1.88-1.28 (m, 7H), 0.96 (t, J=7.2Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 70(11)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.66 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.00 (d, J=8.4 Hz,2H), 7.73 (d, J=8.4 Hz, 2H), 4.34 (s, 2H), 4.04 (dd, J=7.8, 4.5 Hz, 1H),3.96-3.76 (m, 2H), 3.68-3.56 (m, 2H), 3.48-3.38 (m, 2H), 3.36-3.22 (m,4H), 2.52-2.38 (m, 2H), 2.46 (s, 3H), 2.40 (s, 3H), 2.36-2.14 (m, 2H),1.90-1.28 (m, 7H), 1.20-1.08 (m, 6H), 0.97 (t, J=7.5 Hz, 3H), 0.96 (d,J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 70(12)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(2-hydroxyethylaminocarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.88 (d, J=8.7Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.36 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.90-3.76 (m, 2H),3.70 (t, J=6.0 Hz, 2H), 3.56-3.36 (m, 4H), 3.50 (t, J=6.0 Hz, 2H),2.52-2.38 (m, 2H), 2.24-2.08 (m, 2H), 1.88-1.16 (m, 7H), 1.02-0.88 (m,9H).

EXAMPLE 70(13)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.22 (ethyl acetate:methanol 10:1); NMR (CD₃OD):δ 7.59 (d, J=8.4Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4Hz, 2H), 4.38 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.92-3.72 (m, 2H),3.64-3.36 (m, 8H), 2.48-2.10 (m, 4H), 2.04-1.26 (m, 11H), 0.96 (t, J=6.9Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 70(14)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(cyclohexylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.02 (d, J=8.4Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.05 (dd, J=7.8, 4.8 Hz,1H), 3.92-3.72 (m, 2H), 3.68-3.58 (m, 2H), 3.56-3.44 (m, 2H), 3.06 (m,1H), 2.68-2.50 (m, 2H), 2.47 (s, 3H), 2.41 (s, 3H), 2.38-2.08 (m, 2H),1.82-1.06 (m, 25H), 1.02-0.86 (m, 5H).

EXAMPLE 70(15)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-methoxypropylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.02 (dd, J=7.8, 4.8 Hz,1H), 3.94-3.72 (m, 2H), 3.68-3.58 (m, 2H), 3.56-3.46 (m, 2H), 3.39 (t,J=6.0 Hz, 2H), 3.26 (s, 3H), 2.98 (t, J=6.9 Hz, 2H), 2.72-2.58 (m, 2H),2.48 (s, 3H), 2.42 (s, 3H), 2.26-2.10 (m, 2H), 1.90-1.28 (m, 9H),0.98-0.90 (m, 9H).

EXAMPLE 70(16)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylsulfinylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.13 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.88 (d, J=8.7Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 4.47 (s, 2H), 4.02 (dd, J=7.8, 4.8 Hz,1H), 3.96-3.74 (m, 2H), 3.56-3.36 (m, 4H), 2.83 (s, 3H), 2.52-2.34 (m,2H), 2.28-2.08 (m, 2H), 1.90-1.26 (m, 7H), 0.95 (t, J=7.2 Hz, 3H), 0.95(d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 70(17)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-propylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.58 (chloroform:methanol=5:1); NMR (CD₃OD):δ 4.26 (s, 2H), 4.10(t, J=7.2 Hz, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.90-3.68 (m, 2H),3.58-3.36 (m, 4H), 2.58-2.38 (m, 2H), 2.44 (s, 3H), 2.38 (s, 3H),2.30-2.10 (m, 2H), 1.92-1.24 (m, 9H), 0.96 (t, J=7.2 Hz, 6H), 0.96 (d,J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 70(18)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-ethylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.58 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.34-4.24 (m,4H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.92-3.68 (m, 2H), 3.62-3.46 (m, 4H),2.74-2.60 (m, 2H), 2.53 (s, 3H), 2.50 (s, 3H), 2.24-2.06 (m, 2H),1.88-1.26 (m, 10H), 1.02-0.86 (m, 9H).

EXAMPLE 70(19)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclopentylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD):δ 5.00-4.82 (m,1H), 4.31 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz, 1H), 3.92-3.70 (m, 2H),3.62-3.46 (m, 4H), 2.78-2.58 (m, 2H), 2.55 (s, 3H), 2.53 (s, 3H),2.32-2.04 (m, 4H), 2.04-1.26 (m, 13H), 0.98-0.84 (m, 9H).

EXAMPLE 70(20)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.15 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 4.23 (s, 2H),4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.90-3.68 (m, 2H), 3.58-3.36 (m, 4H), 2.56(s, 3H), 2.56-2.38 (m, 2H), 2.32 (s, 3H), 2.32-2.10 (m, 2H), 1.88-1.26(m, 7H), 1.67 (s, 9H), 0.96 (t, J=7.2 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H),0.95 (d, J=6.3 Hz, 3H).

EXAMPLE 70(21)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.17 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.42-7.26 (m,5H), 5.15 (s, 2H), 4.48-4.22 (m, 3H), 4.23 (s, 2H), 4.02 (dd, J=7.8, 4.5Hz, 1H), 3.88-3.68 (m, 2H), 3.58-3.36 (m, 4H), 3.12-2.90 (m, 2H),2.50-1.28 (m, 15H), 2.42 (s, 3H), 2.30 (s, 3H), 0.96 (t, J=6.9 Hz, 3H),0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 70(22)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-((4-methoxyphenyl)methylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.95 (d, J=8.7 Hz,2H), 7.67 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 4.51 (s, 2H), 4.42 (s, 2H), 4.00 (dd, J=7.5, 4.8 Hz, 1H), 3.91-3.72(m, 2H), 3.76 (s, 3H), 3.53-3.35 (m, 4H), 2.50-2.35 (m, 2H), 2.26-2.08(m, 2H), 1.87-1.28 (m, 7H), 0.94 (t, J=7.5 Hz, 3H), 0.94 (d, J=6.6 Hz,3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 70(23)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(3-methoxypropylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.92 (d, J=8.4 Hz,2H), 7.67 (d, J=8.4 Hz, 2H), 4.43 (s, 2H), 4.00 (dd, J=7.8, 4.5 Hz, 1H),3.92-3.75 (m, 2H), 3.53-3.35 (m, 8H), 3.34 (s, 3H), 2.50-2.35 (m, 2H),2.27-2.10 (m, 2H), 1.92-1.28 (m, 9H), 0.94 (t, J=7.2 Hz, 3H), 0.94 (d,J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).

EXAMPLE 70(24)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methoxycarbonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.29 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 8.19 (d, J=9.0Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 4.28 (s, 2H), 4.03 (m, 1H), 3.94 (s,3H), 3.95-3.30 (m, 6H), 2.50-2.15 (m, 4H), 2.44 (s, 3H), 2.39 (s, 3H),1.90-1.30 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H) 0.94(d, J=6.6 Hz, 3H).

EXAMPLE 70(25)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.31 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.37 (d, J=9.0Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 4.02 (m, 1H), 4.00-3.30(m, 6H), 3.86 (s, 3H), 2.65-2.15 (m, 4H), 2.39 (s, 3H), 2.34 (s, 3H),1.90-1.30 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H) 0.94(d, J=6.6 Hz, 3H).

EXAMPLE 70(26)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-(morpholin-4-yl)propylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.18 (ethyl acetate:methanol=3:1); NMR (CD₃OD):δ 8.02 (d, J=8.7Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.10-4.00 (m, 3H),4.00-3.00 (m, 16H), 2.70-2.10 (m, 4H), 2.48 (s, 3H), 2.40 (s, 3H),2.10-1.90 (m, 2H), 1.90-1.30 (m, 7H), 0.96 (t, J=7.2 Hz, 3H), 0.95 (d,J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 70(27)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyrrolidin-1-ylcarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.71-7.59 (m,4H), 4.41 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.83-3.72 (m, 2H), 3.60(t, J=6.9 Hz, 2H), 3.55-3.32 (m, 4H), 3.45 (t, J=6.9 Hz, 2H), 2.57-2.37(m, 2H), 2.27-2.08 (m, 2H), 2.05-1.44 (m, 9H), 1.44-1.27 (m, 2H),0.99-0.90 (m, 9H).

EXAMPLE 70(28)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(piperidin-1-ylcarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.69 (d, J=8.4Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 4.41 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz,1H), 3.93-3.72 (m, 4H), 3.55-3.30 (m, 6H), 2.57-2.39 (m, 2H), 2.26-2.07(m, 2H), 1.90-1.44 (m, 11H), 1.44-1.26 (m, 2H), 0.98-0.90 (m, 9H).

EXAMPLE 70(29)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(morpholin-4-ylcarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.69 (d, J=8.1Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 4.41 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz,1H), 3.93-3.55 (m, 8H), 3.55-3.34 (m, 6H), 2.55-2.36 (m, 2H), 2.27-2.08(m, 2H), 1.88-1.44 (m, 5H), 1.44-1.28 (m, 2H), 0.98-0.90 (m, 9H).

EXAMPLE 70(30)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N-methylN-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.80 (d, J=6.0Hz, 1H), 8.58 (m, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.98 (m, 1H), 7.70 (d,J=7.8 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 4.39 (s, 2H), 4.05-3.95 (m, 3H),3.94-3.69 (m, 2H), 3.60-3.37 (m, 6H), 3.08 (s, 3H), 2.70-2.43 (m, 2H),2.26-2.05 (m, 2H), 1.90-1.44 (m, 5H), 1.44-1.26 (m, 2H), 0.99-0.90 (m,9H).

EXAMPLE 70(31)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(cyclohexylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.92 (d, J=8.1Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 4.43 (s, 2H), 4.01 (dd, J=7.5, 4.5 Hz,1H), 3.96-3.70 (m, 2H), 3.58-3.36 (m, 4H), 2.58-2.38 (m, 2H), 2.28-2.06(m, 2H), 2.04-1.12 (m, 18H), 0.95 (t, J=6.9 Hz, 3H), 0.94 (d, J=6.3 Hz,3H), 0.93 (d, J=6.3 Hz, 3H).

EXAMPLE 70(32)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N,N-dimethylaminosulfonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.91 (d, J=8.7Hz, 2H), 7.86 (d, J=8.7 Hz, 2H), 4.49 (s, 2H), 4.02 (dd, J=7.5, 4.8 Hz,1H), 3.96-3.76 (m, 2H), 3.56-3.38 (m, 4H), 2.72 (s, 6H), 2.60-2.40 (m,2H), 2.28-2.06 (m, 2H), 1.90-1.28 (m, 7H), 0.95 (t, J=7.2 Hz, 3H), 0.95(d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 70(33)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methoxycarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 8.04 (d, J=9.0Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0Hz, 2H), 4.38 (s, 2H), 4.02 (dd, J=7.5, 4.5 Hz, 1H), 3.90 (s, 3H),3.88-3.72 (m, 2H), 3.58-3.36 (m, 4H), 2.58-2.38 (m, 2H), 2.30-2.08 (m,2H), 1.90-1.28 (m, 7H), 0.96 (t, J=6.9 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H),0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 70(34)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.15 (chloroform:methanol=5:1); NMR (CD₃OD):δ 4.56 (m, 1H), 4.20(s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.86-3.42 (m, 8H), 3.30-3.20 (m,2H), 2.93 (s, 3H), 2.64-2.48 (m, 2H), 2.44-2.28 (m, 2H), 2.44 (s, 3H),2.31 (s, 3H), 2.22-2.06 (m, 4H), 1.86-1.28 (m, 7H), 0.98-0.88 (m, 9H).

EXAMPLE 70(35)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylsulfonylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.46 (m, 1H),4.25 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.92-3.68 (m, 4H), 3.60-3.42(m, 4H), 3.04-2.90 (m, 2H), 2.89 (s, 3H), 2.62-2.46 (m, 2H), 2.48 (s,3H), 2.38 (s, 3H), 2.24-1.98 (m, 6H), 1.90-1.28 (m, 7H), 0.98-0.90 (m,9H).

EXAMPLE 70(36)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-(N,N-dimethylamino)propylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.22 (chloroform:methanol:28% aqueous solution ofammonia=100:10:1); NMR (CD₃OD):δ 8.02 (d, J=8.7 Hz, 2H), 7.74 (d, J=8.7Hz, 2H), 4.30 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.84-3.73 (m, 2H),3.66-3.56 (m, 2H), 3.55-3.44 (m, 2H), 3.27-3.18 (m, 2H), 3.02 (t, J=6.3Hz, 2H), 2.89 (s, 6H), 2.70-2.52 (m, 2H), 2.48 (s, 3H), 2.40 (s, 3H),2.28-2.11 (m, 2H), 2.00-1.28 (m, 9H), 1.00-0.90 (m, 9H).

EXAMPLE 70(37)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(N,N-dimethylamino)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.68-7.60 (m,4H), 7.21 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 4.35 (s, 2H), 4.00(dd, J=7.8, 4.8 Hz, 1H), 3.89-3.77 (m, 2H), 3.54-3.40 (m, 4H), 3.28 (s,6H), 2.62-2.44 (m, 2H), 2.26-2.07 (m, 2H), 1.90-1.26 (m, 7H), 1.00-0.90(m, 9H).

EXAMPLE 70(38)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-(N′,N′-dimethylamino)ethyl)aminosulfonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.34 (chloroform:methanol:28% aqueous solution ofammonia=100:10:1); NMR (CD₃OD):δ 8.04 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7Hz, 2H), 4.31 (s, 2H), 4.02 (dd, J=7.8, 4.5 Hz, 1H), 3.95-3.73 (m, 2H),3.66-3.54 (m, 2H), 3.54-3.43 (m, 2H), 3.42 (s, 4H), 3.01 (s, 6H), 2.85(s, 3H), 2.68-2.52 (m, 2H), 2.50 (s, 3H), 2.41 (s, 3H), 2.29-2.10 (m,2H), 1.90-1.28 (m, 7H), 1.00-0.90 (m, 9H).

EXAMPLE 70(39)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-((N,N-dimethylamino)methyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.29 (chloroform:methanol:28%aqueous solution ofammonia=100:10:1); NMR (CD₃OD):δ 7.62 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.7Hz, 2H), 7.18-7.10 (m, 4H), 4.35 (s, 2H), 4.30 (s, 2H), 4.00 (dd,J.=7.8, 4.5 Hz, 1H), 3.88-3.68 (m, 2H), 3.54-3.38 (m, 4H), 2.86 (s, 6H),2.59-2.42 (m, 2H), 2.26-2.07 (m, 2H), 1.88-1.25 (m, 7H), 1.02-0.89 (m,9H).

EXAMPLE 70(40)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.03 (d, J=8.7Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7Hz, 2H), 4.32 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.84-3.64 (m, 2H),3.52-3.35 (m, 4H), 2.48-2.32 (m, 2H), 2.27-2.10 (m, 2H), 1.90-1.44 (m,5H), 1.44-1.26 (m, 2H), 0.99-0.90 (m, 9H).

EXAMPLE 70(41)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylaminocarbonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 4.34 (s, 2H), 4.03 (dd, J=7.8, 4.8 Hz,1H), 3.96-3.74 (m, 2H), 3.70-3.42 (m, 4H), 2.96 (s, 3H), 2.74-2.54 (m,2H), 2.47 (s, 3H), 2.46 (s, 3H), 2.30-2.10 (m, 2H), 1.92-1.28 (m, 7H),0.96 (t, J=6.9 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 70(42)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-((methoxycarbonyl)methylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane

NMR (CDCl₃):δ 7.78 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 6.70 (t,J=4.8 Hz, 1H), 6.40 (brs, 1H), 4.26 (d, J=4.8 Hz, 2H), 3.96 (m, 1H),3.81 (s, 3H), 3.62 (s, 2H), 3.50-3.28 (m, 2H), 3.00-2.48 (m, 8H),2.26-1.20 (m, 7H), 0.99-0.94 (m, 9H).

EXAMPLE 70(43)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-2E-propenyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

NMR (CDCl₃):δ 7.56-7.32 (m, 5H), 6.54 (m, 1H), 6.38 (brs, 1H), 5.96 (m,1H), 4.00 (m, 1H), 3.76-2.90 (m, 8H), 2.38 (s, 3H), 2.34 (s, 3H),2.14-1.22 (m, 11H), 1.00-0.86 (m, 9H).

EXAMPLE 71(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(carboxymethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

To a solution of the compound prepared in Example 70(42) (106 mg) inmethanol (3 ml) was added 5N aqueous solution of sodium hydroxide (0.1ml). The reaction mixture was stirred for 3 hours at room temperature.The reaction mixture was concentrated and the residue was dissolved indioxane. 4N hydrogen chloride/ethyl acetate solution was added to thesolution. The reaction mixture was concentrated and the obtained residuewas added dioxane and filtrated. The filtrate was concentrated and theobtained residue was washed with diethyl ether and dried to give thetitle compound (62 mg) having the following physical data.

TLC: Rf 0.28 (butanol:acetic acid:water=4:2:1); NMR (CD₃OD):δ 7.99 (d,J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 4.44 (s, 2H), 4.11 (s, 2H), 4.02(dd, J=7.5, 4.8 Hz, 1H), 3.94-3.74 (m, 2H), 3.56-3.36 (m, 4H), 2.48-2.32(m, 2H), 2.28-2.08 (m, 2H), 1.88-1.30 (m, 7H), 0.96 (t, J=7.2 Hz, 3H),0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 72(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(3,5-dimethyl-1-phenylpyrazol-4-yl)propyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

To a solution of the compound prepared in Example 70(43) (85 mg) inmethanol (10 ml) solution was added 5% palladium on carbon (10 mg).Under an atmosphere of hydrogen, the reaction mixture was stirred for 22hours at room temperature. The reaction mixture was filtrated throughCelite(brand name) and the filtrate was concentrated. The obtainedresidue was purified by column chromatography on silica gel (ethylacetate:methanol=15:1). To the solution of the obtained compound inmethanol was added 4N hydrogen chloride/ethyl acetate solution. Thereaction mixture was concentrated and the obtained residue was washedwith diethyl ether and dried to give the title compound (23 mg) havingthe following physical data.

TLC: Rf 0.18 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.70-7.50 (m,5H), 4.03 (dd J=7.2, 4.2 Hz, 1H), 3.86-3.68 (m, 2H), 3.66-3.40 (m, 4H),3.30-3.16 (m, 2H), 2.74-2.48 (m, 4H), 2.46 (s, 3H), 2.35 (s, 3H),2.28-1.98 (m, 4H), 1.90-1.24 (m, 7H), 0.97 (t, J=7.2 Hz, 3H), 0.96 (d,J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 73(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(2) instead of the compound prepared inReference example 15, and using[4-(4-formyl-3,5-dimethylpyrazolyl)phenyl]-N,N-dimethylcarboxamideinstead of 3-formyl-6-phenyloxypyridine, the title compound having thefollowing physical data was obtained.

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.62 (d, J=9.0Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 4.32 (s, 2H), 4.05 (dd, J=7.8, 4.5 Hz,1H), 3.96-3.78 (m, 2H), 3.66-3.58 (m, 2H), 3.46-3.34 (m, 2H), 3.13 (s,3H), 3.04 (s, 3H), 2.52-2.38 (m, 2H), 2.42 (s, 3H), 2.39 (s, 3H),2.32-2.14 (m, 2H), 1.82-1.16 (m, 15H), 1.02-0.88 (m, 5H).

EXAMPLE 73(1) TO 73(41)

By the same procedure as described in Example 73 using the correspondingaldehyde derivatives respectively instead of[4-(4-formyl-3,5-dimethylpyrazolyl)phenyl]-N,N-dimethylcarboxamide, thefollowing compounds were obtained.

EXAMPLE 73(1)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.72 (d, J=8.7Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 4.33 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz,1H), 3.98-3.78 (m, 2H), 3.64-3.56 (m, 4H), 3.56-3.44 (m, 2H), 3.44-3.32(m, 2H), 2.50-2.10 (m, 4H), 2.42 (s, 3H), 2.39 (s, 3H), 2.10-1.88 (m,4H), 1.88-1.10 (m, 15H), 1.10-0.90 (m, 5H).

EXAMPLE 73(2)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(morpholin-4-ylcarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.65-7.56 (m,4H), 4.32 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H), 3.96-3.30 (m, 14H),2.54-2.32 (m, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.32-2.12 (m, 2H),1.84-1.10 (m, 15H), 1.02-0.86 (m, 5H).

EXAMPLE 73(3)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.15 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.07 (d, J=8.1Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 4.31 (s, 2H), 4.05 (dd, J=7.2, 5.1 Hz,1H), 3.94-3.76 (m, 2H), 3.79 (t, J=6.0 Hz, 2H), 3.66-3.54 (m, 2H),3.54-3.36 (m, 2H), 3.41 (t, J=6.0 Hz, 2H), 3.00 (s, 6H), 2.66-2.48 (m,2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.28-2.10 (m, 2H), 1.82-1.10 (m, 15H),1.02-0.86 (m, 5H).

EXAMPLE 73(4)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(morpholin-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.59 (d, J=8.4Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.22-7.09 (m, 4H), 4.36 (s, 2H), 4.04(dd, J=7.5, 4.8 Hz, 1H), 3.88-3.34 (m, 14H), 2.52-2.34 (m, 2H),2.28-2.08 (m, 2H), 1.81-1.10 (m, 15H), 1.04-0.84 (m, 5H).

EXAMPLE 73(5)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylsulfonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.08 (d, J=8.4Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 4.50 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.94-3.76 (m, 2H), 3.52-3.36 (m, 4H), 3.15 (s, 3H), 2.56-2.38 (m,2H), 2.26-2.08 (m, 2H), 1.80-1.10 (m, 15H), 1.02-0.86 (m, 5H).

EXAMPLE 73(6)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.95 (d, J=9.0Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.25-7.18 (m, 4H), 4.39 (s, 2H), 4.04(dd, J=7.8, 4.8 Hz, 1H), 3.90-3.76 (m, 2H), 3.58-3.34 (m, 4H), 3.12 (s,3H), 2.50-2.36 (m, 2H), 2.30-2.10 (m, 2H), 1.82-1.10 (m, 15H), 1.02-0.88(m, 5H).

EXAMPLE 73(7)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-(morpholin-4-yl)ethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.06 (d, J=8.7Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.12-4.01 (m, 3H),3.92-3.76 (m, 4H), 3.65-3.40 (m, 6H), 3.40-3.16 (m, 6H), 2.64-2.44 (m,2H), 2.48 (s, 3H), 2.41 (s, 3H), 2.28-2.12 (m, 2H), 1.84-1.10 (m, 15H),1.02-0.86 (m, 5H).

EXAMPLE 73(8)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.08-3.95 (m, 3H),3.95-3.74 (m, 2H), 3.68-3.46 (m, 6H), 3.28-3.20 (m, 2H), 2.91 (s, 3H),2.88-2.72 (m, 2H), 2.70-2.52 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H),2.26-2.08 (m, 2H), 1.82-1.10 (m, 15H), 1.02-0.86 (m, 5H).

EXAMPLE 73(9)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfinylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD):δ7.74 (d, J=9.0 Hz,2H), 7.62 (d, J=8.7 Hz, 2H), 7.25-7.14 (m, 4H), 4.37 (s, 2H), 4.04 (dd,J=7.5, 4.5 Hz, 1H), 3.88-3.72 (m, 2H), 3.54-3.36 (m, 4H), 2.80 (s, 3H),2.52-2.36 (m, 2H), 2.26-2.10 (m, 2H), 1.80-1.10 (m, 15H), 1.02-0.86 (m,5H).

EXAMPLE 73(10)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 4.30 (s, 2H), 4.05 (dd, J=7.5, 4.2 Hz,1H), 3.92-3.68 (m, 4H), 3.66-3.42 (m, 6H), 2.70-2.50 (m, 2H), 2.45 (s,3H), 2.40 (s, 3H), 2.28-2.08 (m, 2H), 1.82-1.10 (m, 15H), 1.02-0.84 (m,5H).

EXAMPLE 73(11)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(2-hydroxyethylaminocarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.89 (d, J=9.0Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.08 (d, J=9.0Hz, 2H), 4.37 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.90-3.70 (m, 2H),3.70 (t, J=6.0 Hz, 2H), 3.58-3.46 (m, 2H), 3.50 (t, J=6.0 Hz, 2H),3.42-3.34 (m, 2H), 2.44-2.30 (m, 2H), 2.30-2.08 (m, 2H), 1.82-1.12 (m,15H), 1.02-0.84 (m, 5H).

EXAMPLE 73(12)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.25(ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.59 (d, J=8.7Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.7Hz, 2H), 4.37 (s, 2H), 4.05 (dd, J=7.5, 4.8 Hz, 1H), 3.90-3.74 (m, 2H),3.62-3.36 (m, 8H), 2.48-2.08 (m, 4H), 2.04-1.08 (m, 19H), 0.96 (t, J=7.2Hz, 3H), 1.04-0.84 (m, 2H).

EXAMPLE 73(13)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(cyclohexylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.03 (d, J=8.7Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.05 (dd, J=7.8, 4.8 Hz,1H), 3.92-3.72 (m, 2H), 3.68-3.58 (m, 2H), 3.56-3.44 (m, 2H), 3.06 (m,1H), 2.68-2.50 (m, 2H), 2.47 (s, 3H), 2.41 (s, 3H), 2.38-2.08 (m, 2H),1.82-1.06 (m, 25H), 1.02-0.86 (m, 5H).

EXAMPLE 73(14)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-methoxypropylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.4Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.05 (dd, J=7.8, 4.8 Hz,1H), 3.92-3.72 (m, 2H), 3.68-3.58 (m, 2H), 3.56-3.46 (m, 4H), 3.39 (t,J=6.0 Hz, 2H), 3.26 (s, 3H), 2.98 (t, J=6.9 Hz, 2H), 2.72-2.56 (m, 2H),2.48 (s, 3H), 2.43 (s, 3H), 2.26-2.08 (m, 2H), 1.82-1.10 (m, 15H),1.02-0.86 (m, 5H).

EXAMPLE 73(15)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylsulfinylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.15 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.85 (d, J=8.7Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 4.47 (s, 2H), 4.05 (dd, J=7.2, 4.8 Hz,1H), 3.94-3.76 (m, 2H), 3.58-3.36 (m, 4H), 2.83 (s, 3H), 2.54-2.34 (m,2H), 2.18-2.06 (m, 2H), 1.82-1.10 (m, 15H), 0.96 (t, J=7.5 Hz, 3H),1.06-0.86 (m, 2H).

EXAMPLE 73(16)((3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-propylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.61 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.28 (s, 2H),4.13 (t, J=7.2 Hz, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H), 3.88-3.72 (m, 2H),3.60-3.38 (m, 4H), 2.62-2.32 (m, 2H), 2.46 (s, 3H), 2.42 (s, 3H),2.28-2.08 (m, 2H), 1.94-1.08 (m, 17H), 0.96 (t, J=7.2 Hz, 6H), 1.06-0.86(m, 2H).

EXAMPLE 73(17)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-ethylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.34-4.20 (m,4H), 4.04 (dd, J=7.8, 4.8 Hz, 1H), 3.88-3.70 (m, 2H), 3.62-3.46 (m, 4H),2.72-2.54 (m, 2H), 2.52 (s, 3H), 2.48 (s, 3H), 2.24-2.06 (m, 2H),1.82-1.08 (m, 18H), 1.02-0.86 (m, 5H).

EXAMPLE 73(18)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclopentylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD):δ 5.02-4.82 (m,1H), 4.33 (s, 2H), 4.04 (dd, J=7.5, 4.8 Hz, 1H), 3.90-3.70 (m, 2H),3.64-3.48 (m, 4H), 2.80-2.60 (m, 2H), 2.58 (s, 3H), 2.57 (s, 3H),2.36-1.08 (m, 25H), 1.04-0.84 (m, 5H).

EXAMPLE 73(19)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-(morpholin-4-yl)propylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.20 (ethyl acetate:methanol=3:1); NMR (CD₃OD):δ 8.02 (d, J=8.7Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.10-4.00 (m, 3H),4.00-3.00 (m, 16H), 2.65-2.10 (m, 4H), 2.47 (s, 3H), 2.40 (s, 3H),2.05-1.95 (m, 2H), 1.85-1.15 (m, 15H), 1.10-0.90 (m, 2H), 0.95 (t, J=7.2Hz, 3H).

EXAMPLE 73(20)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N,N-dimethylaminosulfonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.60 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.90 (d, J=8.4Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 4.48 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz,1H), 3.94-3.76 (m, 2H), 3.56-3.36 (m, 4H), 2.71 (s, 6H), 2.56-2.36 (m,2H), 2.28-2.06 (m, 2H), 1.83-1.10 (m, 15H), 1.08-0.85 (m, 2H), 0.95 (t,J=7.2 Hz, 3H).

EXAMPLE 73(21)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(pyrrolidin-1-ylcarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.68 (d, J=8.7Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 4.41 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz,1H), 3.92-3.73 (m, 2H), 3.60 (t, J=6.9 Hz, 2H), 3.55-3.34 (m, 4H), 3.45(t, J=6.9 Hz, 2H), 2.56-2.36 (m, 2H), 2.27-2.07 (m, 2H), 2.06-1.84 (m,4H), 1.83-1.10 (m, 15H), 1.06-0.83 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 73(22)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(N,N-dimethylamino)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.70-7.62 (m,4H), 7.22 (d, J=9.0 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 4.36 (s, 2H), 4.03(dd, J=7.5, 4.5 Hz, 1H), 3.86-3.70 (m, 2H), 3.52-3.40 (m, 4H), 3.30 (s,6H), 2.62-2.44 (m, 2H), 2.24-2.06 (m, 2H), 1.80-1.14 (m, 15H), 1.02-0.86(m, 5H).

EXAMPLE 73(23)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(cyclohexylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.91 (d, J=8.1Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 4.42 (s, 2H), 4.03 (dd, J=7.5, 4.5 Hz,1H), 3.90-3.72 (m, 3H), 3.52-3.36 (m, 4H), 2.56-2.38 (m, 2H), 2.24-2.06(m, 2H), 2.00-1.10 (m, 25H), 1.04-0.86 (m, 5H).

EXAMPLE 73(24)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methoxycarbonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.33 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 8.18 (d, J=8.7Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.05 (m, 1H), 3.94 (s,3H), 3.94-3.45 (m, 6H), 2.70-2.50 (m, 2H), 2.46 (s, 3H), 2.41 (s, 3H),2.30-2.10 (m, 2H), 1.85-1.10 (m, 15H), 1.10-0.90 (m, 2H), 0.95 (t, J=6.9Hz, 3H).

EXAMPLE 73(25)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(3-methoxypropylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.18 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.93 (d, J=8.4Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 4.44 (s, 2H), 4.04 (dd, J=7.5, 4.8 Hz,1H), 3.92-3.74 (m, 2H), 3.58-3.36 (m, 10H), 3.35 (s, 3H), 2.54-2.36 (m,2H), 2.28-2.06 (m, 2H), 1.94-1.08 (m, 15H), 1.04-0.84 (m, 2H), 0.95 (t,J=6.9 Hz, 3H).

EXAMPLE 73(26)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.27 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 8.81 (m, 1H),8.59 (m, 1H), 8.16-7.94 (m, 2H), 7.71 (d, J=7.8 Hz, 2H), 7.42 (d, J=7.8Hz, 2H), 4.40 (s, 2H), 4.06-3.70 (m, 5H), 3.60-3.36 (m, 6H), 3.09 (s,3H), 2.72-2.42 (m, 2H), 2.26-2.02 (m, 2H), 1.84-1.14 (m, 15H), 1.06-0.84(m, 2H), 0.95 (t, J=6.9 Hz, 3H).

EXAMPLE 73(27)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-((4-methoxyphenyl)methylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.96 (d, J=9.0Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0Hz, 2H), 4.52 (s, 2H), 4.43 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H),3.92-3.78 (m, 2H), 3.77 (s, 3H), 3.56-3.36 (m, 4H), 2.52-2.34 (m, 2H),2.26-2.06 (m, 2H), 1.82-1.10 (m, 15H), 1.06-0.84 (m, 2H), 0.95 (t, J=7.2Hz, 3H).

EXAMPLE 73(28)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methoxycarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.04 (d, J=9.0Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0Hz, 2H), 4.38 (s, 2H), 4.05 (dd, J=7.5, 4.5 Hz, 1H), 3.90 (s, 3H),3.88-3.72 (m, 2H), 3.58-3.38 (m, 4H), 2.58-2.38 (m, 2H), 2.28-2.08 (m,2H), 1.84-1.08 (m, 15H), 1.06-0.86 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 73(29)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.42 (d, J=9.0Hz, 2H), 7.12 (d, J=9.0 Hz, 2H), 4.33 (s, 2H), 4.06 (dd, J=7.5, 4.5 Hz,1H), 3.96-3.76 (m, 2H), 3.88 (s, 3H), 3.68-3.40 (m, 4H), 2.68-2.48 (m,2H), 2.45 (s, 3H), 2.38 (s, 3H), 2.32-2.08 (m, 2H), 1.84-1.12 (m, 15H),1.06-0.84 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).

EXAMPLE 73(30)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.18 (chloroform:methanol=5:1); NMR (CD₃OD):δ 4.58 (m, 1H), 4.21(s, 2H), 4.03 (dd, J=7.5, 4.5 Hz, 1H), 3.86-3.42 (m, 8H), 3.32-3.20 (m,2H), 2.93 (s, 3H), 2.70-2.50 (m, 2H), 2.50-2.26 (m, 2H), 2.45 (s, 3H),2.33 (s, 3H), 2.24-2.04 (m, 4H), 1.82-1.06 (m, 15H), 1.02-0.86 (m, 5H).

EXAMPLE 73(31)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-methylsulfonylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.44 (m, 1H),4.24 (s, 2H), 4.04 (dd, J=7.8, 4.8 Hz, 1H), 3.92-3.68 (m, 4H), 3.60-3.40(m, 4H), 3.02-2.90 (m, 2H), 2.89 (s, 3H), 2.60-2.40 (m, 2H), 2.46 (s,3H), 2.36 (s, 3H), 2.26-1.96 (m, 6H), 1.82-1.10 (m, 15H), 1.02-0.86 (m,5H).

EXAMPLE 73(32)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-(N,N-dimethylamino)propylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.22 (chloroform:methanol:28% aqueous solution ofammonia=100:10:1); NMR (CD₃OD):δ 8.02 (d, J=8.7 Hz, 2H), 7.74 (d, J=8.7Hz, 2H), 4.30 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.94-3.73 (m, 2H),3.66-3.56 (m, 2H), 3.54-3.43 (m, 2H), 3.27-3.18 (m, 2H), 3.05-2.97 (m,2H), 2.89 (s, 6H), 2.68-2.51 (m, 2H), 2.48 (s, 3H), 2.40 (s, 3H),2.28-2.08 (m, 2H), 2.00-1.88 (m, 2H), 1.84-1.10 (m, 15H), 1.04-0.88 (m,5H).

EXAMPLE 73(33)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-(N′,N′-dimethylamino)ethyl)aminosulfonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.32 (chloroform:methanol:28% aqueous solution ofammonia=100:10:1); NMR (CD₃OD):δ 8.04 (d, J=8.7 Hz, 2H), 7.82 (d, J=8.7Hz, 2H), 4.30 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.94-3.74 (m, 2H),3.67-3.56 (m, 2H), 3.55-3.45 (m, 2H), 3.42 (s, 4H), 3.01 (s, 6H), 2.85(s, 3H), 2.72-2.53 (m, 2H), 2.50 (s, 3H), 2.41 (s, 3H), 2.27-2.08 (m,2H), 1.84-1.11 (m, 15H), 1.06-0.84 (m, 5H).

EXAMPLE 73(34)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(piperidin-1-ylcarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.56 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.68 (d, J=8.1Hz, 2H), 7.50 (d, J=8.1 Hz, 2H), 4.41 (s, 2H), 4.04 (dd, J=7.5, 4.8 Hz,1H), 3.92-3.65 (m, 4H), 3.56-3.30 (m, 6H), 2.57-2.36 (m, 2H), 2.26-2.07(m, 2H), 1.83-1.10 (m, 21H), 1.06-0.83 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 73(35)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(morpholin-4-ylcarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.69 (d, J=8.1Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 4.41 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz,1H), 3.91-3.55 (m, 8H), 3.55-3.30 (m, 6H), 2.57-2.37 (m, 2H), 2.27-2.05(m, 2H), 1.83-1.08 (m, 15H), 1.06-0.83 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 73(36)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-((N,N-dimethylamino)methyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.37 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.62 (d, J=8.7Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.16-7.10 (m, 4H), 4.35 (s, 2H), 4.31(s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.86-3.70 (m, 2H), 3.52-3.38 (m,4H), 2.86 (s, 6H), 2.62-2.46 (m, 2H), 2.26-2.06 (m, 2H), 1.82-1.12 (m,15H), 1.06-0.88 (m, 5H).

EXAMPLE 73(37)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methylaminocarbonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.13 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 8.00 (d, J=8.7Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 4.33 (s, 2H), 4.06 (dd, J=7.8, 4.8 Hz,1H), 3.94-3.76 (m, 2H), 3.66-3.56 (m, 2H), 3.52-3.40 (m, 2H), 2.95 (s,3H), 2.62-2.38 (m, 2H), 2.50 (s, 3H), 2.42 (s, 3H), 2.32-2.10 (m, 2H),1.84-1.18 (m, 15H), 1.06-0.84 (m, 2H), 0.97 (t, J=6.9 Hz, 3H).

EXAMPLE 73(38)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.38 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 4.25 (s, 2H),4.04 (dd, J=7.8, 4.8 Hz, 1H), 3.88-3.73 (m, 2H), 3.59-3.50 (m, 2H),3.47-3.42 (m, 2H), 2.60 (s, 3H), 2.57-2.45 (m, 2H), 2.38 (s, 3H),2.23-2.10 (m, 2H), 1.80-1.15 (m, 24H), 1.02-0.92 (m, 5H).

EXAMPLE 73(39)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-benzyl-oxycarbonylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.33 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.39-7.29 (m,5H), 5.14 (s, 2H), 4.52 (m, 1H), 4.33-4.29 (m, 2H), 4.25 (s, 2H), 4.04(dd, J=7.8, 4.8 Hz, 1H), 3.87-3.72 (m, 2H), 3.55-3.42 (m, 4H), 3.10-2.98(m, 2H), 2.60-2.43 (m, 5H), 2.36 (s, 3H), 2.23-1.95 (m, 6H), 1.80-1.15(m, 15H), 1.02-0.92 (m, 5H).

EXAMPLE 73(40)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-hydroxymethylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane

TLC: Rf 0.24 (chloroform:methanol=20:1); NMR (CD₃OD):δ 7.34 (d, J=8.7Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7Hz, 2H), 4.57 (s, 2H), 4.00 (dd, J=7.5, 4.5 Hz, 1H), 3.55 (s, 2H),3.47-3.38 (m, 2H), 2.93-2.74 (m, 4H), 2.24-2.04 (m, 2H), 2.00-1.83 (m,2H), 1.83-1.08 (m, 15H), 1.05-0.84 (m, 2H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 73(41)(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-((methoxycarbonyl)methylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane

NMR (CDCl₃):δ 7.78 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 6.71 (t,J=4.8 Hz, 1H), 6.32 (brs, 1H), 4.26 (d, J=4.8 Hz, 2H), 4.00 (m, 1H),3.81 (s, 3H), 3.64 (s, 2H), 3.54-3.28 (m, 2H), 3.06-2.72 (m, 8H),2.26-1.10 (m, 15H), 1.06-0.82 (m, 2H), 0.94 (t, J=6.9 Hz, 3H).

EXAMPLE 74(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(carboxymethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 71 using the compoundprepared in Example 73(41) instead of the compound prepared in Example70(42), the title compound having the following physical data wasobtained.

TLC: Rf 0.36 (butanol:acetic acid:water=4:2:1); NMR (CD₃OD):δ 7.99 (d,J=8.1 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 4.45 (s, 2H), 4.11 (s, 2H), 4.04(dd, J=7.2, 4.5 Hz, 1H), 3.94-3.74 (m, 2H), 3.58-3.36 (m, 4H), 2.56-2.34(m, 2H), 2.30-2.06 (m, 2H), 1.84-1.16 (m, 15H), 1.06-0.86 (m, 2H), 0.96(t, J=7.2 Hz, 3H).

EXAMPLE 75(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-phenyloxyphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(3) instead of the compound prepared inReference example 15, using 4-phenyloxybenzaldehyde instead of3-formyl-6-phenyloxypyridine, the title compound having the followingphysical data was obtained.

TLC: Rf 0.46 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.50 (d, J=8.7Hz, 2H), 7.42-7.37 (m, 2H), 7.18 (m, 1H), 7.07-7.01 (m, 4H), 4.31 (s,2H), 4.15 (d, J=2.1 Hz, 1H), 3.97 (m, 1H), 3.71 (m, 1H), 3.60-3.05 (m,5H), 2.55-1.90 (m, 6H), 1.90-1.60 (m, 5H), 1.60-1.10 (m, 6H), 1.10-0.90(m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(1) TO 75(71)

By the same procedure as described in Example 75 using the correspondingaldehyde derivatives respectively instead of 4-phenyloxybenzaldehyde,the following compounds having the following physical data wereobtained.

EXAMPLE 75(1)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(6-phenyloxypyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.36 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 8.28 (d, J=2.7Hz, 1H), 8.01 (dd, J=8.4, 2.7 Hz, 1H), 7.43 (t, J=8.4 Hz, 2H), 7.25 (t,J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 4.38 (s,2H), 4.15 (d, J=1.8 Hz, 1H), 4.02 (m, 1H), 3.77 (m, 1H), 3.60-3.05 (m,5H), 2.55-1.90 (m, 6H), 1.90-1.60 (m, 5H), 1.60-1.10 (m, 6H), 1.10-0.90(m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(2)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-fluorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.54-7.48 (m, 2H),7.14 (dd, J=9.6, 8.1 Hz, 2H), 7.09-7.02 (m, 4H), 4.33 (s, 2H), 4.15 (d,J=2.1 Hz, 1H), 4.00 (m, 1H), 3.73 (m, 1H), 3.57-3.40 (m, 3H), 3.33-3.08(m, 2H), 2.54-1.88 (m, 6H), 1.82-1.63 (m, 5H), 1.48-1.12 (m, 6H),1.03-0.85 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(3)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-chlorophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.58-7.51 (m, 2H),7.38 (d, J=9.3 Hz, 2H), 7.09 (brd, J=8.4 Hz, 2H), 7.02 (d, J=9.3 Hz,2H), 4.34 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 3.99 (m, 1H), 3.73 (m, 1H),3.58-3.40 (m, 3H), 3.32-3.09 (m, 2H), 2.53-1.89 (m, 6H), 1.81-1.62 (m,5H), 1.48-1.13 (m, 6H), 1.03-0.82 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(4)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-cyanophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.52 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.74 (d, J=9.0 Hz,2H), 7.64-7.58 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.13 (d, J=9.0 Hz, 2H),4.38 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.02 (m, 1H), 3.77 (m, 1H),3.57-3.43 (m, 3H), 3.33-3.08 (m, 2H), 2.54-1.90 (m, 6H), 1.80-1.63 (m,5H), 1.48-1.13 (m, 6H), 1.03-0.82 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(5)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.53 (d, J=8.7 Hz,2H), 7.29 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.7 Hz,2H), 4.33 (s, 2H), 4.15 (d, J=1.8 Hz, 1H), 3.98 (m, 1H), 3.73 (m, 1H),3.58-3.40 (m, 3H), 3.32-3.03 (m, 2H), 2.95 (s, 3H), 2.52-2.24 (m, 3H),2.17-1.88 (m, 3H), 1.80-1.62 (m, 5H), 1.48-1.08 (m, 6H), 1.03-0.82 (m,2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(6)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.21 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 8.54 (d, J=3.0Hz, 1H), 8.08 (m, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 2H),7.28 (d, J=9.0 Hz, 2H), 4.39 (s, 2H), 4.10 (d, J=2.1 Hz, 1H), 4.01 (m,1H), 3.75 (m, 1H), 3.60-3.20 (m, 5H), 2.73 (s, 3H), 2.70-2.35 (m, 3H),2.20-1.90 (m, 3H), 1.90-1.60 (m, 5H), 1.50-1.15 (m, 6H), 1.10-0.90 (m,2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(7)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(1-methylethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.45 (d, J=8.1Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 4.30 (s, 2H), 4.15 (d, J=2.1 Hz, 1H),3.98 (m, 1H), 3.72 (m, 1H), 3.60-3.05 (m, 5H), 2.95 (quint, J=6.9 Hz,1H), 2.50-1.90 (m, 6H), 1.85-1.60 (m, 5H), 1.50-1.10 (m, 6H), 1.25 (d,J=6.9 Hz, 6H), 1.10-0.90 (m, 2H), 0.95 (t, J=6.9 Hz, 3H).

EXAMPLE 75(8)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.32 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.74 (d, J=9.0 Hz,2H), 7.61 (d, J=9.0 Hz, 2H), 7.22 (d, J=9.0 Hz, 2H), 7.17 (d, J=9.0 Hz,2H), 4.36 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.00 (dt, J=3.6, 12.6 Hz,1H), 3.75 (dt, J=3.6, 12.6 Hz, 1H), 3.58-3.42 (m, 3H), 3.32-3.13 (m,2H), 2.80 (s, 3H), 2.54-2.25 (m, 3H), 2.17-1.88 (m, 3H), 1.80-1.63 (m,5H), 1.49-1.13 (m, 6H), 1.02-0.82 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(9)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3,4,5,6-tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.45 (d, J=9.0Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 4.63 (m, 1H), 4.28 (s, 2H), 4.15 (d,J=2.0 Hz, 1H), 4.01-3.90 (m, 3H), 3.72 (m, 1H), 3.63-3.53 (m, 2H),3.50-3.41 (m, 3H), 3.27 (m, 1H), 3.15(m, 1H), 2.50-1.91 (m, 8H),1.68-1.65 (m, 7H), 1.39-1.15 (m, 6H), 1.01-0.87 (m, 5H).

EXAMPLE 75(10)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-phenylcarbonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.75 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.87 (d, J=7.5Hz, 2H), 7.81-7.72 (m, 4H), 7.67 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.5 Hz,2H), 4.48 (s, 2H), 4.16 (d, J=2.0 Hz, 1H), 4.07 (m, 1H), 3.81 (m, 1H),3.53-3.47 (m, 3H), 3.33-3.17 (m, 2H), 2.51-2.31 (m, 3H), 2.17-1.92 (m,3H), 1.76-1.70 (m, 5H), 1.40-1.15 (m, 6H), 1.01-0.87 (m, 5H).

EXAMPLE 75(11)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(1-phenyl-1-hydroxymethyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.57 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.53 (d, J=8.0Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.39-7.20 (m, 5H), 5.81 (s, 1H), 4.33(s, 2H), 4.14 (d, J=2.0 Hz, 1H), 4.00 (m, 1H), 3.74 (m, 1H), 3.45-3.41(m, 3H), 3.26 (m, 1H), 3.10 (m, 1H), 2.48-1.91 (m, 6H), 1.80-1.60 (m,5H), 1.44-1.14 (m, 6H), 1.00-0.86 (m, 5H).

EXAMPLE 75(12)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(morpholin-4-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.95 (d, J=8.7Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.1 Hz, 1H),4.04 (m, 1H), 3.79 (m, 1H), 3.75-3.67 (m, 4H), 3.64-3.49 (m, 3H),3.35-3.18 (m, 2H), 3.05-2.97 (m, 4H), 2.66-2.34 (m, 3H), 2.49 (s, 3H),2.40 (s, 3H), 2.20-1.87 (m, 3H), 1.84-1.60 (m, 5H), 1.52-1.10 (m, 6H),1.05-0.80 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(13)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylaminosulfonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.36 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.16 (d, J=2.0 Hz, 1H),4.05 (m, 1H), 3.80 (m, 1H), 3.63-3.53 (m, 3H), 3.34-3.23 (m, 2H),2.59-2.34 (m, 3H), 2.57 (s, 3H), 2.46 (s, 3H), 2.39 (s, 3H), 2.16 (m,1H), 2.05-1.93 (m, 2H), 1.77-1.66 (m, 5H), 1.45-1.17 (m, 6H), 1.01-0.88(m, 5H).

EXAMPLE 75(14)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.98 (d, J=8.7Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.0 Hz, 1H),4.04 (m, 1H), 3.78 (m, 1H), 3.69 (t, J=5.7 Hz, 2H), 3.64-3.50 (m, 3H),3.38-3.24 (m, 2H), 3.19 (t, J=5.7 Hz, 2H), 2.87 (s, 3H), 2.60-2.34 (m,3H), 2.47 (s, 3H), 2.40 (s, 3H), 2.20-1.88 (m, 3H), 1.82-1.60 (m, 5H),1.50-1.12 (m, 6H), 1.04-0.82 (m, 5H).

EXAMPLE 75(15)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(pyridin-2-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.40 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 8.51 (d, J=4.5Hz, 1H), 8.01 (m, 1H), 7.80 (d, J=8.0Hz, 1H), 7.41 (m, 1H), 4.32 (s,2H), 4.16 (d, J=2.0 Hz, 1H), 4.05 (m, 1H), 3.80 (m, 1H), 3.60-3.49 (m,3H), 3.33-3.10 (m, 2H), 2.67 (s, 3H), 2.53-2.35 (m, 3H), 2.41 (s, 3H),2.16 (m, 1H), 2.05-1.93 (m, 2H), 1.80-1.65 (m, 5H), 1.50-1.15 (m, 6H),1.01-0.88 (m, 5H).

EXAMPLE 75(16)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.34 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 4.32(m, 1H),4.27 (s, 2H), 4.15 (d, J=2.0 Hz, 1H), 4.00 (m, 1H), 3.73 (m, 1H),3.60-3.50 (m, 3H), 3.37-3.20 (m, 2H), 2.58-2.40 (m, 9H), 2.13-1.70 (m,15H), 1.58-1.15 (m, 9H), 1.01-0.88 (m, 5H).

EXAMPLE 75(17)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(1,3,5-trimethylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.27 (s, 2H),4.15 (d, J=2.1 Hz, 1H), 3.98 (m, 1H), 3.85 (s, 3H), 3.73 (m, 1H),3.62-3.56 (m, 3H), 3.40-3.20 (m, 2H), 2.60 (m, 1H), 2.50-2.36 (m, 2H),2.45 (s, 3H), 2.41 (s, 3H), 2.16-1.88 (m, 3H), 1.84-1.60 (m, 5H),1.50-1.10 (m, 6H), 1.04-0.80 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(18)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.19 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.62 (d, J=9.0Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 4.32 (s, 2H), 4.17 (d, J=2.0 Hz, 1H),4.05 (m, 1H), 3.80 (m, 1H), 3.60-3.53 (m, 3H), 3.33-3.27 (m, 2H), 3.13(s, 3H), 3.04 (s, 3H), 2.53-2.35 (m, 3H), 2.42 (s, 3H), 2.39 (s, 3H),2.17 (m, 1H), 2.05-1.92 (m, 2H), 1.77-1.65 (m, 5H), 1.39-1.15 (m, 6H),1.01-0.88 (m, 5H).

EXAMPLE 75(19)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N,N-bismethylsulfonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.47 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.69 (d, J=8.4Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 4.42 (s, 2H), 4.16 (d, J=2.1 Hz, 1H),4.06 (m, 1H), 3.80 (m, 1H), 3.60-3.10 (m, 5H), 3.46 (s, 6H), 2.55-1.90(m, 6H), 1.90-1.60 (m, 5H), 1.50-1.10 (m, 6H), 1.10-0.90 (m, 2H), 0.95(t, J=6.9 Hz, 3H).

EXAMPLE 75(20)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylsulfonylaminophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecan.2hydrochloride

TLC: Rf 0.30 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.48-7.38 (m, 4H),4.30 (s, 2H), 4.17 (d, J=2.1 Hz, 1H), 4.03 (m, 1H), 3.78 (m, 1H),3.62-3.49 (m, 3H), 3.37-3.21 (m, 2H), 3.04 (s, 3H), 2.62-2.35 (m, 3H),2.40 (s, 3H), 2.38 (s, 3H), 2.18-1.90 (m, 3H), 1.83-1.63 (m, 5H),1.48-1.13 (m, 6H), 1.03-0.82 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(21)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.36 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.96 (d, J=8.7 Hz,2H), 7.77 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.17 (d, J=2.1 Hz, 1H), 4.05(m, 1H), 3.79 (m, 1H), 3.63-3.48 (m, 3H), 3.34-3.15 (m, 2H), 2.74 (s,6H), 2.58-2.32 (m, 3H), 2.47 (s, 3H), 2.40 (s, 3H), 2.21-1.90 (m, 3H),1.82-1.62 (m, 5H), 1.48-1.13 (m, 6H), 1.03-0.82 (m, 2H), 0.96 (t, J=7.2Hz, 3H).

EXAMPLE 75(22)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.38 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.72 (d, J=8.7 Hz,2H), 7.59 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.4 Hz, 1H), 4.04(m, 1H), 3.78 (m, 1H), 3.65-3.47 (m, 3H), 3.62 (t, J=6.6 Hz, 2H), 3.50(t, J=6.6 Hz, 2H), 3.33-3.18 (m, 2H), 2.60-2.32 (m, 3H), 2.43 (s, 3H),2.39 (s, 3H), 2.20-1.87 (m, 7H), 1.82-1.62 (m, 5H), 1.48-1.13 (m, 6H),1.03-0.82 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(23)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(morpholin-4-ylcarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.38 (chloroform:methanol=9:1); NMR (CD₃OD):δ 7.65-7.57 (m, 4H),4.31 (s, 2H), 4.17 (d, J=2.4 Hz, 1H), 4.04 (m, 1H), 3.85-3.46 (m, 12H),3.34-3.17 (m, 2H), 2.60-2.32 (m, 3H), 2.43 (s, 3H), 2.39 (s, 3H),2.20-1.90 (m, 3H), 1.82-1.62 (m, 5H), 1.48-1.13 (m, 6H), 1.03-0.82 (m,2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(24)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-aminocarbonylphenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.40 (ethyl acetate:methanol=3:1); NMR (CD₃OD):δ 7.99 (d, J=8.4Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 4.44 (s, 2H), 4.16 (d, J=2.1 Hz, 1H),4.04 (m, 1H), 3.78 (m, 1H), 3.60-3.38 (m, 3H), 3.30-3.08 (m, 2H),2.60-2.24 (m, 3H), 2.20-1.86 (m, 3H), 1.82-1.58 (m, 5H), 1.50-1.06 (m,6H), 1.04-0.80 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(25)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-aminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.90 (d, J=8.7Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.36 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.02 (m, 1H), 3.76 (m,1H), 3.56-3.42 (m, 3H), 3.33-2.99 (m, 2H), 2.54-1.88 (m, 6H), 1.81-1.60(m, 5H), 1.48-1.12 (m, 6H), 1.04-0.81 (m, 5H).

EXAMPLE 75(26)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-aminosulfonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.89 (d, J=8.7Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.7Hz, 2H), 4.36 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.01 (m, 1H), 3.75 (m,1H), 3.58-3.42 (m, 3H), 3.32-3.14 (m, 2H), 2.55-2.40 (m, 2H), 2.32 (m,1H), 2.13 (m, 1H), 2.07-1.89 (m, 2H), 1.82-1.60 (m, 5H), 1.50-1.12 (m,6H), 1.06-0.80 (m, 5H).

EXAMPLE 75(27)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-1-oxido-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.62 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.51 (s, 1H),7.80-7.56 (m, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 4.39(s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.78 (m, 1H), 3.62-3.40(m, 3H), 3.36-3.18 (m, 2H), 2.64-2.30 (m, 3H), 2.63 (s, 3H), 2.20-1.86(m, 3H), 1.84-1.58 (m, 5H), 1.52-1.08 (m, 6H), 1.04-0.82 (m, 2H), 0.96(t, J=7.2 Hz, 3H).

EXAMPLE 75(28)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-hydroxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.46 (d, J=9.0Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0Hz, 2H), 4.30 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 3.98 (m, 1H), 3.72 (m,1H), 3.67-3.39 (m, 3H), 3.27 (m, 1H), 3.15 (m, 1H), 2.53-2.35 (m, 2H),2.26 (m, 1H), 2.18-1.87 (m, 3H), 1.84-1.60 (m, 5H), 1.51-1.05 (m, 6H),1.04-0.80 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(29)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.34 (d, J=8.7Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 4.34 (s, 2H), 4.16 (d, J=2.1 Hz, 1H),4.04 (m, 1H), 3.79 (m, 1H), 3.65-3.50 (m, 3H), 3.32 (m, 1H), 3.29 (m,1H), 2.64 (m, 1H), 2.55-2.42 (m, 2H), 2.48 (s, 3H), 2.38 (s, 3H),2.20-1.88 (m, 3H), 1.83-1.60 (m, 5H), 1.52-1.05 (m, 6H), 1.04-0.81 (m,2H), 0.96 (t, J=6.9 Hz, 3H).

EXAMPLE 75(30)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.32 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.03 (d, J=8.7Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.17 (d, J=2.1 Hz, 1H),4.06 (m, 1H), 3.80 (m, 1H), 3.62-3.48 (m, 5H), 3.38-3.18 (m, 2H), 3.01(t, J=5.7 Hz, 2H), 2.58-2.30 (m, 3H), 2.46 (s, 3H), 2.39 (s, 3H),2.20-1.88 (m, 3H), 1.82-1.62 (m, 5H), 1.50-1.10 (m, 6H), 1.02-0.82 (m,5H).

EXAMPLE 75(31)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.59 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.17 (d, J=2.4 Hz, 1H),4.06 (m, 1H), 3.80 (m, 1H), 3.62-3.48 (m, 3H), 3.38-3.18 (m, 6H),2.60-2.30 (m, 3H), 2.47 (s, 3H), 2.39 (s, 3H), 2.20-1.88 (m, 3H),1.82-1.60 (m, 9H), 1.50-1.10 (m, 6H), 1.02-0.82 (m, 5H).

EXAMPLE 75(32)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(5-chloro-3-methyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.52 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.62-7.46 (m,5H), 4.34 (s, 2H), 4.17 (d, J=1.8 Hz, 1H), 4.10 (m, 1H), 3.83 (m, 1H),3.66-3.47 (m, 3H), 3.39-3.13 (m, 2H), 2.60-2.28 (m, 3H), 2.44 (s, 3H),2.18 (m, 1H), 2.09-1.88 (m, 2H), 1.85-1.62 (m, 5H), 1.54-1.13 (m, 6H),1.03-0.81 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).

EXAMPLE 75(33)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.49 (d, J=8.7Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.02-6.92 (m, 4H), 4.30 (s, 2H), 4.15(d, J=2.1 Hz, 1H), 3.97 (m, 1H), 3.79 (s, 3H), 3.72 (m, 1H), 3.58-3.38(m, 3H), 3.30-3.13 (m, 2H), 2.55-2.40 (m, 2H), 2.32 (m, 1H), 2.16-1.86(m, 3H), 1.81-1.60 (m, 5H), 1.50-1.10 (m, 6H), 1.03-0.80 (m, 2H), 0.95(t, J=7.2 Hz, 3H).

EXAMPLE 75(34)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3-methoxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.54 (d, J=8.7Hz, 2H), 7.28 (m, 1H), 7.70 (d, J=8.7 Hz, 2H), 6.75 (ddd, J=8.7, 2.1,1.2 Hz, 1H), 6.63-6.56 (m, 2H), 4.33 (s, 2H), 4.15 (d, J=2.1 Hz, 1H),3.98 (m, 1H), 3.77 (s, 3H), 3.75 (m, 1H), 3.58-3.40 (m, 3H), 3.30-3.11(m, 2H), 2.55-2.23 (m, 3H), 2.17-1.88 (m, 3H), 1.81-1.59 (m, 5H),1.50-1.06 (m, 6H), 1.03-0.80 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(35)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N,N-dimethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.66 (d, J=8.4Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 4.41 (s, 2H), 4.15 (d, J=1.8 Hz, 1H),4.04 (m, 1H), 3.78 (m, 1H), 3.59-3.42 (m, 3H), 3.30-3.10 (m, 2H), 3.11(s, 3H), 2.99 (s, 3H), 2.53-2.20 (m, 3H), 2.14 (m, 1H), 2.08-1.88 (m,2H), 1.83-1.60 (m, 5H), 1.52-1.10 (m, 6H), 1.06-0.80 (m, 2H), 0.95 (t,J=7.2 Hz, 3H).

EXAMPLE 75(36)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.63-7.43 (m,5H), 4.32 (s, 2H), 4.17 (d, J=2.1 Hz, 1H), 4.04 (m, 1H), 3.79 (m, 1H),3.64-3.49 (m, 3H), 3.30-3.20 (m, 2H), 2.70-2.30 (m, 9H), 2.20-1.88 (m,3H), 1.83-1.58 (m, 5H), 1.52-1.06 (m, 6H), 1.06-0.80 (m, 2H), 0.96 (t,J=7.2 Hz, 3H).

EXAMPLE 75(37)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.37 (d, J=8.7Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 4.30 (s, 2H), 4.17 (d, J=2.1 Hz, 1H),4.04 (m, 1H), 3.79 (m, 1H), 3.63-3.47 (m, 3H), 3.35-3.06 (m, 2H),2.63-2.26 (m, 3H), 2.43 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H), 2.16 (m,1H), 2.09-1.88 (m, 2H), 1.83-1.60 (m, 5H), 1.55-1.10 (m, 6H), 1.08-0.80(m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(38)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-fluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.50 (dd, J=8.4,4.8 Hz, 2H), 7.30 (dd, J=8.4, 8.4 Hz, 2H), 4.30 (s, 2H), 4.17 (d, J=2.1Hz, 1H), 4.04 (m, 1H), 3.78 (m, 1H), 3.63-3.45 (m, 3H), 3.30-3.12 (m,2H), 2.61-2.30 (m, 3H), 2.37 (s, 3H), 2.36 (s, 3H), 2.16 (m, 1H),2.08-1.88 (m, 2H), 1.82-1.60 (m, 5H), 1.52-1.07 (m, 6H), 1.04-0.80 (m,2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(39)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(6-(4-methoxyphenyloxy)pyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.36 (m, 1H),8.12 (m, 1H), 7.12-6.98 (m, 5H), 4.39 (s, 2H), 4.15 (d, J=2.1 Hz, 1H),4.00 (m, 1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.60-3.42 (m, 3H), 3.30-3.16(m, 2H), 2.58-2.30 (m, 3H), 2.16-1.86 (m, 3H), 1.80-1.62 (m, 5H),1.50-1.10 (m, 6H), 1.02-0.80 (m, 5H).

EXAMPLE 75(40)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.95 (d, J=9.0Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.25-7.16 (m, 4H), 4.38 (s, 2H), 4.15(d, J=2.4 Hz, 1H), 4.02 (m, 1H), 3.76 (m, 1H), 3.60-3.44 (m, 3H),3.30-3.10 (m, 2H), 3.11 (s, 3H), 2.54-2.26 (m, 3H), 2.18-1.88 (m, 3H),1.82-1.62 (m, 5H), 1.50-1.10 (m, 6H), 1.02-0.82 (m, 5H).

EXAMPLE 75(41)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(2-(N,N-dimethylamino)ethylaminocarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.15 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.93 (d, J=9.0 Hz,2H), 7.62 (d, J=8.4 Hz, 2H), 7.20-7.08 (m, 4H), 3.98 (s, 2H), 4.16 (d,J=2.1 Hz, 1H), 3.98 (m, 1H), 3.75 (m, 1H), 3.75 (t, J=5.4 Hz, 2H),3.58-3.42 (m, 3H), 3.38 (t, J=5.4 Hz, 2H), 3.30-3.18 (m, 2H), 2.98 (s,6H), 2.56-2.28 (m, 3H), 2.18-1.88 (m, 3H), 1.82-1.62 (m, 5H), 1.46-1.14(m, 6H), 1.02-0.84 (m, 5H).

EXAMPLE 75(42)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.4 Hz, 1H),4.04 (m, 1H), 3.80 (m, 1H), 3.73 (t, J=6.0 Hz, 2H), 3.72-3.48 (m, 5H),3.30-3.16 (m, 2H), 2.60-2.30 (m, 3H), 2.43 (s, 3H), 2.39 (s, 3H),2.22-1.88 (m, 3H), 1.80-1.62 (m, 5H), 1.50-1.12 (m, 6H), 1.06-0.82 (m,5H).

EXAMPLE 75(43)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.14 (chloroform:methanol:28% aqueous solution ofammonia=200:20:1); NMR (CD₃OD):δ 8.07 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.7Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.1 Hz, 1H), 4.04 (m, 1H), 3.79 (t,J=5.7 Hz, 2H), 3.78 (m, 1H), 3.63-3.49 (m, 3H), 3.41 (t, J=5.7 Hz, 2H),3.32-3.20 (m, 2H), 3.00 (s, 6H), 2.63-2.35 (m, 3H), 2.45 (s, 3H), 2.39(s, 3H), 2.20-1.90 (m, 3H), 1.82-1.63 (m, 5H), 1.48-1.13 (m, 6H),1.03-0.82 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(44)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(morpholin-4-yl)ethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.07 (d, J=9.0Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 4.30 (s, 2H), 4.17 (d, J=2.4 Hz, 1H),4.12-3.96 (m, 3H), 3.90-3.70 (m, 4H), 3.62-3.48 (m, 6H), 3.20-3.16 (m,6H), 2.70-2.30 (m, 3H), 2.49 (s, 3H), 2.41 (s, 3H), 2.20-1.88 (m, 3H),1.82-1.62 (m, 5H), 1.50-1.10 (m, 6H), 1.04-0.84 (m, 5H).

EXAMPLE 75(45)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(morpholin-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.31 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.58 (d, J=8.4Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.18-7.06 (m, 4H), 4.36 (s, 2H), 4.16(d, J=2.4 Hz, 1H), 4.00 (m, 1H), 3.82-3.40 (m, 12H), 3.38-3.12 (m, 2H),2.52-2.24 (m, 3H), 2.18-1.86 (m, 3H), 1.82-1.62 (m, 5H), 1.50-1.10 (m,6H), 1.02-0.82 (m, 5H).

EXAMPLE 75(46)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.05 (d, J=2.1Hz, 1H), 7.00-6.90 (m, 2H), 4.26 (s, 4H), 4.23 (s, 2H), 4.15 (d, J=1.8Hz, 1H), 3.94 (m, 1H), 3.68 (m, 1H), 3.58-3.34 (m, 3H), 3.30-3.08 (m,2H), 2.50-1.86 (m, 6H), 1.80-1.62 (m, 5H), 1.50-1.04 (m, 6H), 1.02-0.82(m, 5H).

EXAMPLE 75(47)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.99 (d, J=9.0Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.1 Hz, 1H),4.06 (m, 1H), 3.78 (m, 1H), 3.62-3.48 (m, 3H), 3.34-3.14 (m, 6H),2.60-2.30 (m, 3H), 2.45 (s, 3H), 2.39 (s, 3H), 2.20-1.88 (m, 3H),1.82-1.62 (m, 5H), 1.50-1.08 (m, 6H), 1.15 (t, J=7.5 Hz, 6H), 1.02-0.82(m, 5H).

EXAMPLE 75(48)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(pyridin-1-oxido-3-yloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.10 (ethyl acetate:methanol=3:1); NMR (CD₃OD):δ δ 8.48-8.37 (m,2H), 7.73 (d, J=9.0 Hz, 2H), 7.73-7.60 (m, 2H), 7.31 (d, J=9.0 Hz, 2H),4.39 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.01 (m, 1H), 3.76 (m, 1H),3.60-3.20 (m, 5H), 2.70-2.40 (m, 3H), 2.20-1.90 (m, 3H), 1.90-1.60 (m,5H), 1.60-1.10 (m, 6H), 1.10-0.80 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 75(49)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.01 (d, J=8.7Hz, 2H), 7.85 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.4 Hz, 1H),4.10-3.94 (m, 3H), 3.78 (m, 1H), 3.66-3.56 (m, 5H), 3.40-3.20 (m, 4H),2.91 (s, 3H), 2.88-2.72 (m, 2H), 2.70-2.40 (m, 3H), 2.50 (s, 3H), 2.40(s, 3H), 2.20-1.88 (m, 3H), 1.84-1.60 (m, 5H), 1.56-1.10 (m, 6H),1.04-0.82 (m, 5H).

EXAMPLE 75(50)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.84 (d, J=9.0Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.07 (d, J=9.0Hz, 2H), 4.36 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.74 (m,1H), 3.60-3.44 (m, 3H), 3.28-3.16 (m, 2H), 2.91 (s, 3H), 2.52-2.26 (m,3H), 2.18-1.88 (m, 3H), 1.82-1.62 (m, 5H), 1.50-1.10 (m, 6H), 1.02-0.82(m, 5H).

EXAMPLE 75(51)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(2,4-difluorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.63 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.56 (m, 1H),7.33-7.16 (m, 2H), 4.32 (s, 2H), 4.18 (d, J=2.4 Hz, 1H), 4.04 (m, 1H),3.80 (m, 1H), 3.64-3.46 (m, 3H), 3.30-3.16 (m, 2H), 2.62-1.88 (m, 6H),2.39 (s, 3H), 2.28 (s, 3H), 1.84-1.60 (m, 5H), 1.52-1.10 (m, 6H),1.06-0.82 (m, 2H), 0.97 (t, J=6.9 Hz, 3H).

EXAMPLE 75(52)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.21 (chloroform:methanol:28% aqueous solution ofammonia=100:10:1); NMR (CD₃OD):δ 8.07 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.1 Hz, 1H), 4.04 (m, 1H), 3.80 (m,1H), 3.64-3.50 (m, 3H), 3.40-3.22 (m, 6H), 2.96 (s, 6H), 2.74-2.38 (m,3H), 2.49 (s, 3H), 2.41 (s, 3H), 2.22-1.88 (m, 3H), 1.84-1.60 (m, 5H),1.52-1.10 (m, 6H), 1.06-0.82 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(53)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylaminocarbonylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.21 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.98 (d, J=8.7Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 4.31 (s, 2H), 4.16 (d, J=2.1 Hz, 1H),4.04 (m, 1H), 3.79 (m, 1H), 3.64-3.49 (m, 3H), 3.37-3.20 (m, 2H), 2.94(s, 3H), 2.63-2.33 (m, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.16 (m, 1H),2.09-1.90 (m, 2H), 1.83-1.62 (m, 5H), 1.50-1.12 (m, 6H), 1.04-0.82 (m,5H).

EXAMPLE 75(54)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.43 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.05 (d, J=9.0 Hz,2H), 7.61 (d, J=9.0 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz,2H), 4.38 (s, 2H), 4.17 (d, J=2.1 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H),3.60-3.40 (m, 3H), 3.30-3.10 (m, 2H), 2.56-1.86 (m, 6H), 1.82-1.60 (m,5H), 1.52-1.16 (m, 6H), 1.06-0.82 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).

EXAMPLE 75(55)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-((4-methoxyphenyl)methylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.96 (d, J=8.4Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4Hz, 2H), 4.52 (s, 2H), 4.43 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.02 (m,1H), 3.77 (s, 3H), 3.77 (m, 1H), 3.58-3.38 (m, 3H), 3.30-3.10 (m, 2H),2.54-2.22 (m, 3H), 2.18-1.86 (m, 3H), 1.82-1.60 (m, 5H), 1.50-1.08 (m,6H), 1.04-0.80 (m, 2H), 0.95 (t, J=6.9 Hz, 3H).

EXAMPLE 75(56)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3-methoxypropylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.27 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.93 (d, J=8.1Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 4.43 (s, 2H), 4.16 (d, J=1.8 Hz, 1H),4.04 (m, 1H), 3.78 (m, 1H), 3.60-3.40 (m, 7H), 3.35 (s, 3H), 3.30-3.10(m, 2H), 2.58-1.60 (m, 13H), 1.52-1.08 (m, 6H), 1.06-0.80 (m, 2H), 0.96(t, J=7.2 Hz, 3H).

EXAMPLE 75(57)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.22 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.80 (m, 1H),8.57 (m, 1H), 8.08 (m, 1H), 7.96 (m, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.43(d, J=8.4 Hz, 2H), 4.40 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.06-3.90 (m,3H), 3.80 (m, 1H), 3.62-3.38 (m, 5H), 3.30-3.10 (m, 2H), 3.08 (s, 3H),2.64-2.30 (m, 3H), 2.18-1.84 (m, 3H), 1.82-1.60 (m, 5H), 1.50-1.06 (m,6H), 1.04-0.80 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(58)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.59-7.56 (m,4H), 7.15 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 4.36 (s, 2H), 4.15(d, J=2.0 Hz, 1H), 4.01 (m, 1H), 3.75 (m, 1H), 3.60-3.46 (m, 7H),3.30-3.13 (m, 2H), 2.51-2.11 (m, 4H), 2.04-1.89 (m, 6H), 1.80-1.65 (m,5H), 1.50-1.15 (m, 6H), 1.00-0.87 (m, 5H).

EXAMPLE 75(59)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-chlorophenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.58 (d, J=9.0Hz, 2H), 7.49 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 4.17 (d, J=2.1 Hz, 1H),4.04 (m, 1H), 3.78 (m, 1H), 3.62-3.48 (m, 3H), 3.30-3.16 (m, 2H),2.62-2.32 (m, 3H), 2.40 (s, 3H), 2.39 (s, 3H), 2.22-1.86 (m, 3H),1.84-1.60 (m, 5H), 1.54-1.10 (m, 6H), 1.06-0.82 (m, 2H), 0.97 (t, J=7.2Hz, 3H).

EXAMPLE 75(60)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-trifluoromethylphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.88 (d, J=8.7Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 4.33 (s, 2H), 4.18 (d, J=2.1 Hz, 1H),4.04 (m, 1H), 3.80 (m, 1H), 3.64-3.46 (m, 3H), 3.30-3.16 (m, 2H),2.62-2.28 (m, 3H), 2.46 (s, 3H), 2.40 (s, 3H), 2.24-1.88 (m, 3H),1.84-1.60 (m, 5H), 1.56-1.06 (m, 6H), 1.06-0.82 (m, 2H), 0.97 (t, J=7.2Hz, 3H).

EXAMPLE 75(61)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.40 (d, J=8.7Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 4.18 (d, J=2.4 Hz, 1H),4.04 (m, 1H), 3.88 (s, 3H), 3.80 (m, 1H), 3.66-3.48 (m, 3H), 3.30-3.18(m, 2H), 2.64-2.30 (m, 3H), 2.42 (s, 3H), 2.36 (s, 3H), 2.22-1.88 (m,3H), 1.84-1.60 (m, 5H), 1.54-1.10 (m, 6H), 1.06-0.82 (m, 2H), 0.97 (t,J=7.2 Hz, 3H).

EXAMPLE 75(62)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-ethylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.27 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.28 (s, 2H),4.23 (q, J=7.2 Hz, 2H), 4.17 (d, J=2.4 Hz, 1H), 4.00 (m, 1H), 3.78 (m,1H), 3.64-3.44 (m, 3H), 3.30-3.18 (m, 2H), 2.70-2.34 (m, 3H), 2.48 (s,3H), 2.43 (s, 3H), 2.22-1.86 (m, 3H), 1.84-1.60 (m, 5H), 1.52-1.08 (m,6H), 1.43 (t, J=7.2 Hz, 3H), 1.06-0.80 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(63)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-propylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.31 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.28 (s, 2H),4.16 (d, J=2.4 Hz, 1H), 4.15 (t, J=7.2 Hz, 2H), 4.00 (m, 1H), 3.76 (m,1H), 3.62-3.46 (m, 3H), 3.30-3.18 (m, 2H), 2.66-2.36 (m, 3H), 2.47 (s,3H), 2.43 (s, 3H), 2.20-1.60 (m, 10H), 1.52-1.10 (m, 6H), 1.18 (t, J=7.2Hz, 3H), 1.06-0.80 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 75(64)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.26 (s, 2H),4.17 (d, J=2.4 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.62-3.46 (m, 3H),3.30-3.22 (m, 2H), 2.64-2.40 (m, 3H), 2.63 (s, 3H), 2.42 (s, 3H),2.20-1.86 (m, 3H), 1.84-1.62 (m, 5H), 1.72 (s, 9H), 1.54-1.16 (m, 6H),1.04-0.82 (m, 2H), 0.96 (t, J=6.9 Hz, 3H).

EXAMPLE 75(65)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclopentylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.27 (s, 2H),4.16 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.78 (m, 1H), 3.64-3.44 (m, 4H),3.30-3.20 (m, 2H), 2.66-2.36 (m, 3H), 2.47 (s, 3H), 2.42 (s, 3H),2.28-1.60 (m, 16H), 1.58-1.10 (m, 6H), 1.08-0.82 (m, 2H), 0.96 (t, J=6.9Hz, 3H).

EXAMPLE 75(66)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(2-phenylethyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.36-7.18 (m,3H), 7.16-7.00 (m, 2H), 4.39 (t, J=6.3 Hz, 2H), 4.18 (s, 2H), 4.17 (d,J=2.4 Hz, 1H), 3.88 (m, 1H), 3.72-3.46 (m, 2H), 3.42-3.22 (m, 4H), 3.12(t, J=6.3 Hz, 2H), 2.66-2.34 (m, 3H), 2.44 (s, 3H), 2.18-1.86 (m, 3H),1.92 (s, 3H), 1.84-1.62 (m, 5H), 1.54-1.10 (m, 6H), 1.06-0.82 (m, 2H),0.97 (t, J=6.9 Hz, 3H).

EXAMPLE 75(67)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1-benzyl-oxycarbonylpiperidin-4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.42-7.25 (m,5H), 5.14 (s, 2H), 4.56 (m, 1H), 4.36-4.25 (m, 2H), 4.25 (s, 2H), 4.15(d, J=2.1 Hz, 1H), 3.98 (m, 1H), 3.73 (m, 1H), 3.62-3.45 (m, 3H),3.40-3.20 (m, 2H), 3.18-2.94 (m, 2H), 2.67-2.30 (m, 9H), 2.20-1.85 (m,7H), 1.83-1.58 (m, 5H), 1.50-1.08 (m, 6H), 1.05-0.80 (m, 2H), 0.95 (t,J=7.2 Hz, 3H).

EXAMPLE 75(68)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(cyclohexylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD): 7.92 (d, J=8.7 Hz,2H), 7.67 (d, J=8.7 Hz, 2H), 4.42 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.02(m, 1H), 3.92-3.69 (m, 2H), 3.60-3.39 (m, 3H), 3.30-3.12 (m, 2H),2.56-2.26 (m, 3H), 2.17-1.58 (m, 14H), 1.51-1.08 (m, 10H), 1.06-0.80 (m,2H), 0.95 (t, J=6.9 Hz, 3H).

EXAMPLE 75(69)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1-methylsulfonylpiperidin4-yl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.26 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.48 (m, 1H),4.25 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.05-3.83 (m, 3H), 3.74 (m, 1H),3.60-3.46 (m, 3H), 3.40-3.20 (m, 2H), 3.05-2.92 (m, 2H), 2.90 (s, 3H),2.60 (m, 1H), 2.52-2.40 (m, 2H), 2.49 (s, 3H), 2.39 (s, 3H), 2.26-1.88(m, 7H), 1.84-1.60 (m, 5H), 1.50-1.10 (m, 6H), 1.05-0.80 (m, 2H), 0.95(t, J=6.9 Hz, 3H).

EXAMPLE 75(70)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(2-hydroxyethylaminocarbonyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.50 (chloroform:methanol=5:1); NMR (CD₃OD):δ 7.89 (d, J=9.0 Hz,2H), 7.60 (d, J=9.0 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz,2H), 4.37 (s, 2H), 4.17 (d, J=2.1 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H),3.71 (t, J=5.7 Hz, 2H), 3.60-3.40 (m, 3H), 3.51 (t, J=5.7 Hz, 2H),3.30-3.10 (m, 2H), 2.58-1.84 (m, 6H), 1.82-1.56 (m, 5H), 1.54-1.06 (m,6H), 1.04-0.80 (m, 2H), 0.96 (t, J=6.9 Hz, 3H).

EXAMPLE 75(71)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-hydroxymethylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane

TLC: Rf 0.37 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.34 (d, J=8.7Hz, 4H), 6.97 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 4.57 (s, 2H),4.13 (d, J=2.1 Hz, 1H), 3.71 (s, 2H), 3.47 (m, 1H), 3.35 (dd, J=9.0, 2.1Hz, 1H), 3.30-2.88 (m, 5H), 2.31-1.81 (m, 6H), 1.81-1.58 (m, 5H),1.55-1.05 (m, 6H), 1.05-0.83 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 76(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(9) instead of the compound prepared inReference example 15, and using4-(4-methylsulfonylaminophenyloxy)benzaldehyde instead of3-formyl-6-phenyloxypyridine, the title compound having the followingphysical data was obtained.

TLC: Rf 0.54 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.54 (d, J=8.4Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.06 (d, j=8.4 Hz, 2H), 7.03 (d, J=8.7Hz, 2H), 4.32 (s, 2H), 4.15 (d, J=2.0 Hz, 1H), 3.98 (m, 1H), 3.73 (m,1H), 3.55-3.43 (m, 3H), 3.30-3.16 (m, 2H), 2.95 (s, 3H), 2.52-2.28 (m,3H), 2.14-1.91 (m, 3H), 1.76-1.65 (m, 5H), 1.50-1.15 (m, 6H), 1.00-0.86(m, 5H).

EXAMPLE 77(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(4) instead of the compound prepared inReference example 15, and using 4-formyl-3,5-dimethyl-1-phenylpyrazoleinstead of 3-formyl-6-phenyloxypyridine, the title compound having thefollowing physical data was obtained.

TLC: Rf 0.31 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.67-7.56 (m,5H), 4.37 (s, 2H), 4.13 (d, J=2.0 Hz, 1H), 4.06 (m, 1H), 3.98-3.91 (m,2H), 3.80 (m, 1H), 3.64-3.53 (m, 4H), 3.46-3.37 (m, 3H), 2.80-2.52 (m,5H), 2.45 (s, 3H), 2.16-2.01 (m, 2H), 1.91-1.82 (m, 2H), 1.71 (m, 1H),1.50-1.17 (m, 6H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 77(1) TO 77(5)

By the same procedure as described in Example 77 using the correspondingaldehyde derivatives respectively instead of4-formyl-3,5-dimethyl-1-phenylpyrazole, the following compounds havingthe following physical data were obtained.

EXAMPLE 77(1)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.84 (d, J=8.7Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.36 (s, 2H), 4.12 (d, J=2.0 Hz, 1H), 4.06-3.90 (m, 3H), 3.75(m, 1H), 3.56-3.34 (m, 5H), 3.30-3.20 (m, 2H), 2.91 (s, 3H), 2.51-2.28(m, 3H), 2.16-1.69 (m, 5H), 1.50-1.15 (m, 5H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 77(2)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-(4-methoxyphenylmethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.95 (d, J=8.3Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 4.51 (s, 2H), 4.42 (s, 2H), 4.11 (d, J=2.0 Hz, 1H), 4.04-3.91(m, 3H), 3.76 (m, 1H), 3.76 (s, 3H), 3.56-3.37 (m, 5H), 3.30-3.13 (m,2H), 2.50-1.70 (m, 8H), 1.39-1.15 (m, 5H), 0.95 (t, J=7.0 Hz, 3H).

EXAMPLE 77(3)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminocarbonyl)phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.55 (chloroform:methanol=4:1); NMR (CD₃OD):δ 7.63 (d, J=9.0 Hz,2H), 7.60 (d, J=9.0 Hz, 2H), 4.32 (s, 2H), 4.13 (d, J=2.0 Hz, 1H), 4.06(m, 1H), 4.00-3.91 (m, 2H), 3.79 (m, 1H), 3.63-3.52 (m, 4H), 3.46-3.34(m, 3H), 3.13 (s, 3H), 3.04 (s, 3H), 2.62-2.37 (m, 2H), 2.44 (s, 3H),2.41 (s, 3H), 2.15 (m, 1H), 2.03 (m, 1H), 1.90-1.70 (m, 3H), 1.50-1.15(m, 6H), 0.96 (t, J=7.0 Hz, 3H).

EXAMPLE 77(4)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.30 (chloroform:methanol=4:1); NMR (CD₃OD):δ 8.04 (d, J=9.0 Hz,2H), 7.60 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.07 (d, J=9.0 Hz,2H), 4.37 (s, 2H), 4.12 (d, J=2.0 Hz, 1H), 4.08-3.93 (m, 3H), 3.75 (m,1H), 3.57-3.34 (m, 5H), 3.30-3.15 (m, 2H), 2.52-1.69 (m, 8H), 1.50-1.18(m, 5H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 77(5)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.35 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.53 (d, J=8.7Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.7Hz, 2H), 4.33 (s, 2H), 4.12 (d, J=2.0 Hz, 1H), 4.04-3.92 (m, 3H), 3.72(m, 1H), 3.54-3.38 (m, 5H), 3.30-3.13 (m, 2H), 2.95 (s, 3H), 2.51-2.26(m, 3H), 2.16-2.00 (m, 2H), 1.89-1.70 (m, 3H), 1.50-1.15 (m, 5H), 0.95(t, J=7.0 Hz, 3H).

EXAMPLE 78(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(5) instead of the compound prepared inReference example 15, and using 4-formyl-3,5-dimethyl-1-phenylpyrazoleinstead of 3-formyl-6-phenyloxypyridine, title compound having thefollowing physical data was obtained.

TLC: Rf 0.45 (ethyl acetate:methanol=4:1); NMR (CD₃OD):δ 7.64-7.51 (m,5H), 4.34 (s, 2H), 4.05 (m, 1H), 4.01 (d, J=2.0 Hz, 1H), 3.79 (m, 1H),3.63-3.52 (m, 3H), 3.39 (dd, J=9.9, 2.0 Hz, 1H), 3.30 (m, 1H), 2.64 (m,1H), 2.48 (m, 1H), 2.47 (s, 3H), 2.42 (s, 3H), 2.37-2.12 (m, 2H),1.90-1.82 (m, 2H), 1.74-1.15 (m, 11H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 78(1) TO 78(3)

By the same procedure as described in Example 78 using the correspondingaldehyde derivatives respectively instead of4-formyl-3,5-dimethyl-1-phenylpyrazole, the following compounds wereobtained.

EXAMPLE 78(1)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-(4-methoxyphenylmethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.96 (d, J=8.7Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 4.52 (s, 2H), 4.42 (s, 2H), 4.02 (m, 1H), 4.00 (d, J=1.8 Hz,1H), 3.77 (s, 3H), 3.77 (m, 1H), 3.60-3.02 (m, 5H), 2.58-2.04 (m, 5H),2.00-1.06 (m, 12H), 0.96 (t, J=7.5 Hz, 3H).

EXAMPLE 78(2)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.85 (d, J=8.7Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.7Hz, 2H), 4.37 (s, 2H), 4.02 (m, 1H), 4.01 (d, J=2.1 Hz, 1H), 3.78 (m,1H), 3.40-3.12 (m, 5H), 2.92 (s, 3H), 2.60-2.06 (m, 5H), 2.00-1.08 (m,12H), 0.96 (t, J=7.2 Hz, 3H).

EXAMPLE 78(3)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=5:1); NMR (CD₃OD):δ 8.05 (d, J=8.7 Hz,2H), 7.61 (d, J=8.7 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.7 Hz,2H), 4.38 (s, 2H), 4.02 (m, 1H), 4.01 (d, J=1.8 Hz, 1H), 3.78 (m, 1H),3.62-3.08 (m, 5H), 2.60-2.06 (m, 5H), 2.00-1.08 (m, 12H), 0.96 (t, J=6.9Hz, 3H).

EXAMPLE 79(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(6) instead of the compound prepared inReference example 15, using4-(4-methylaminocarobonylphenyloxy)benzaldehyde instead of3-formyl-6-phenyloxypyridine, the title compound having the followingphysical data was obtained.

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.84 (d, J=9.0Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 7.07 (d, J=9.0Hz, 2H), 4.36 (s, 2H), 4.14 (d, J=1.8 Hz, 1H), 3.99 (m, 1H), 3.74 (m,1H), 3.55-3.40 (m, 3H), 3.20 (m, 1H), 3.19 (dd, J=9.6, 1.8 Hz, 1H), 2.91(s, 3H), 2.59-2.29 (m, 3H), 2.12 (m, 1H), 2.00 (m, 1H), 1.74 (m, 1H),1.46 (m, 1H), 0.99 (d, J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.93 (t,J=7.5 Hz, 3H).

EXAMPLE 79(1) AND 79(2)

By the same procedure as described in Example 79 using the correspondingaldehyde derivatives respectively instead of4-(4-methylaminocarobonylphenyloxy)benzaldehyde, the following compoundswere obtained.

EXAMPLE 79(1)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.40 (m, 1H),4.30 (s, 2H), 4.14 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.76 (m, 1H),3.59-3.43 (m, 3H), 3.22 (m, 1H), 3.20 (dd, J=9.6, 2.1 Hz, 1H), 2.66 (m,1H), 2.53 (s, 3H), 2.49 (s, 3H), 2.50-2.38 (m, 2H), 2.15-1.10 (m, 14H),0.99 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 79(2)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenylmethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.95 (d, J=8.7Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7Hz, 2H), 4.51 (s, 2H), 4.42 (s, 2H), 4.13 (d, J=2.1 Hz, 1H), 4.01 (m,1H), 3.76 (m, 1H), 3.76 (s, 3H), 3.54-3.39 (m, 3H), 3.19 (m, 1H), 3.18(dd, J=9.6, 2.1 Hz, 1H), 2.58-2.26 (m, 3H), 2.10 (m, 1H), 1.99 (m, 1H),1.72 (m, 1H), 1.46 (m, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz,3H), 0.92 (t, J=7.5 Hz, 3H).

EXAMPLE 80(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(7) instead of the compound prepared inReference example 15, and using4-(4-methylaminocarobonylphenyloxy)benzaldehyde instead of3-formyl-6-phenyloxypyridine, the title compound having the followingphysical data was obtained.

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.84 (d, J=9.0Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0Hz, 2H), 4.36 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 3.99 (m, 1H), 3.75 (m,1H), 3.54-3.39 (m, 3H), 3.30-3.10 (m, 2H), 2.91 (s, 3H), 2.56-2.27 (m,3H), 2.18-1.88 (m, 3H), 1.83-1.60 (m, 5H), 1.46 (m, 1H), 1.37-1.11 (m,3H), 1.04-0.80 (m, 2H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 80(1) TO 80(5)

By the same procedure as described in Example 80 using the correspondingaldehyde derivatives respectively instead of4-(4-methylaminocarobonylphenyloxy)benzaldehyde, the following compoundswere obtained.

EXAMPLE 80(1)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.39 (m, 1H),4.29 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.76 (m, 1H),3.60-3.42 (m, 3H), 3.40-3.20 (m, 2H), 2.65 (m, 1H), 2.53 (s, 3H), 2.49(s, 3H), 2.53-2.35 (m, 2H), 2.15-1.05 (m, 22H), 1.05-0.80 (m, 2H), 0.93(t, J=7.2 Hz, 3H).

EXAMPLE 80(2)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenylmethylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.94 (d, J=8.7Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7Hz, 2H), 4.51 (s, 2H), 4.41 (s, 2H), 4.14 (d, J=1.8 Hz, 1H), 4.01 (m,1H), 3.76 (m, 1H), 3.76 (s, 3H), 3.54-3.38 (m, 3H), 3.27 (dd, J=9.6, 1.8Hz, 1H), 3.18 (m, 1H), 2.57-2.26 (m, 3H), 2.16-1.86 (m, 3H), 1.82-1.60(m, 5H), 1.54-1.05 (m, 4H), 1.03-0.80 (m, 2H), 0.92 (t, J=7.5 Hz, 3H).

EXAMPLE 80(3)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminocarbonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.63 (s, 4H),4.32 (s, 2H), 4.16 (d, J=2.1 Hz, 1H), 4.04 (m, 1H), 3.79 (m, 1H),3.64-3.43 (m, 3H), 3.34-3.20 (m, 2H), 3.13 (s, 3H), 3.04 (s, 3H), 2.62(m, 1H), 2.53-2.39 (m, 2H), 2.45 (s, 3H), 2.44 (s, 3H), 2.19-1.88 (m,3H), 1.83-1.60 (m, 5H), 1.46 (m, 1H), 1.38-1.10 (m, 3H), 1.05-0.80 (m,2H), 0.95 (t, J=7.5 Hz, 3H).

EXAMPLE 80(4)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.21 (chloroform:methanol:acetic acid=20:2:1); NMR (CD₃OD):δ8.04 (d, J=9.0 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H),7.07 (d, J=9.0 Hz, 2H), 4.37 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.01 (m,1H), 3.75 (m, 1H), 3.55-3.38 (m, 3H), 3.30-3.09 (m, 2H), 2.55-2.26 (m,3H), 2.18-1.88 (m, 3H), 1.83-1.60 (m, 5H), 1.57-1.10 (m, 4H), 1.04-0.80(m, 2H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 80(5)(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxycarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.03 (d, J=8.7Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.37 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.00 (m, 1H), 3.88 (s,3H), 3.75 (m, 1H), 3.54-3.41 (m, 3H), 3.30-3.10 (m, 2H), 2.58-2.27 (m,3H), 2.18-1.87 (m, 3H), 1.84-1.61 (m, 5H), 1.56-1.08 (m, 4H), 1.04-0.80(m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 81(3R)-1-propyl-2,5-dioxo-3-(1-cyclohexylmethylidene)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 71 using the compoundprepared in Example 80(5) instead of the compound prepared in Example70(42), the title compound having the following physical data wasobtained.

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.03 (d, J=8.7Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 5.87 (d, J=10.5 Hz, 1H), 4.37 (s, 2H), 3.78-3.62 (m, 2H),3.58-3.38 (m, 4H), 2.54-2.36 (m, 3H), 2.27-2.15 (m, 2H), 1.80-1.51 (m,7H), 1.50-1.08 (m, 5H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 82(3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Reference example 13→Referenceexample 14→Example 67→Reference example 15→Example 68 using thecorresponding amino acid derivative instead of(2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy4-methylpentanoic acid, andusing the corresponding amine derivative instead of n-butylamine, andusing the corresponding aldehyde derivative instead of3-formyl-6-phenyloxypyridine, the title compound having the followingphysical data was obtained.

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.39-4.27 (m,1H), 4.28 (s, 2H), 4.01 (dd, J=7.8, 4.5 Hz, 1H), 3.92-3.68 (m, 2H),3.61-3.50 (m, 2H), 3.47-3.38 (m, 2H), 2.68-2.50 (m, 2H), 2.49 (s, 3H),2.45 (s, 3H), 2.25-2.05 (m, 2H), 2.03-1.20 (m, 15H), 0.98-0.89 (m, 9H).

EXAMPLE 82(1) TO 82(6)

By the same procedure as described in Example 82 using the correspondingaldehyde derivatives respectively instead of1-cyclohexyl-4-formyl-3,5-dimethylpyrazole, the following compoundshaving the following physical data were obtained.

EXAMPLE 82(1)(3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.53 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.53 (d, J=8.7Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.03 (d, J=9.0Hz, 2H), 4.34 (s, 2H), 4.01 (dd, J=7.8, 4.8 Hz, 1H), 3.90-3.69 (m, 2H),3.55-3.43 (m, 2H), 3.39-3.30 (m, 2H), 2.95 (s, 3H), 2.48-2.29 (m, 2H),2.28-2.09 (m, 2H), 1.90-1.44 (m, 5H), 0.94 (d, J=6.6 Hz, 3H), 0.93 (d,J=6.6 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 82(2)(3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminosulfonyl)phenyl)pyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.3hydrochloride

TLC: Rf 0.09 (chloroform:methanol:acetic acid=10:5:1); NMR (CD₃OD):δ8.07 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 4.02 (dd,J=7.8, 4.5 Hz, 1H), 3.95-3.73 (m, 2H), 3.66-3.56 (m, 2H), 3.50-3.40 (m,2H), 3.35-3.20 (m, 4H), 2.95 (s, 6H), 2.72-2.53 (m, 2H), 2.49 (s, 3H),2.41 (s, 3H), 2.30-2.08 (m, 2H), 1.92-1.45 (m, 5H), 0.99-0.89 (m, 9H).

EXAMPLE 82(3)(3S)-1-propyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.57 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.43-4.25 (m,1H), 4.29 (s, 2H), 4.04 (dd, J=7.8, 4.5 Hz, 1H), 3.92-3.70 (m, 2H),3.60-3.50 (m, 2H), 3.48-3.38 (m, 2H), 2.70-2.50 (m, 2H), 2.51 (s, 3H),2.47 (s, 3H), 2.25-2.03 (m, 2H), 2.03-1.40 (m, 19H), 1.40-1.08 (m, 4H),1.05-0.83 (m, 2H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 82(4)(3S)-1-propyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.55 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.53 (d, J=9.0Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 7.03 (d, J=9.0Hz, 2H), 4.33 (s, 2H), 4.04 (dd, J=7.5, 4.5 Hz, 1H), 3.89-3.69 (m, 2H),3.54-3.43 (m, 2H), 3.39-3.30 (m, 2H), 2.95 (s, 3H), 2.50-2.30 (m, 2H),2.28-2.06 (m, 2H), 1.83-1.40 (m, 10H), 1.40-1.10 (m, 3H), 1.05-0.85 (m,2H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 82(5)1-butyl-2,5-dioxo-9-(4-(4-methylsulfonylaminophenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.54 (d, J=8.7Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.7Hz, 2H), 4.32 (s, 2H), 3.97 (s, 2H), 3.77-3.62 (m, 2H), 3.55-3.35 (m,4H), 2.95 (s, 3H), 2.48-2.33 (m, 2H), 2.33-2.22 (m, 2H), 1.60-1.46 (m,2H), 1.43-1.26 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

EXAMPLE 82(6)1-butyl-2,5-dioxo-9-(3,5-dimethyl-1-cyclohexylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.34 (m, 1H),4.27 (s, 2H), 3.97 (s, 2H), 3.78-3.65 (m, 2H), 3.62-3.47 (m, 4H),2.65-2.50 (m, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 2.31-2.20 (m, 2H),2.04-1.70 (m, 6H), 1.65-1.42 (m, 4H), 1.42-1.20 (m, 4H), 0.94 (t, J=7.2Hz, 3H).

EXAMPLE 83(3R)-1-(2-butynyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Reference example 13→Referenceexample 14→Example 67 using(2R,3R)-2-(t-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoic acidinstead of (2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoicacid, 2-butynylamine instead of n-butylamine,N-(3,5-dimethyl-1-phenylpyrazol-4-yl)methyl-4-piperidone instead ofN-benzyl-4-piperidone, and n-butylisonitrile instead ofbenzylisonitrile, the title compound having the following physical datawas obtained.

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.60-7.45 (m,5H), 4.44-4.28 (m, 3H), 4.21 (d, J=2.1 Hz, 1H), 4.10-3.94 (m, 2H), 3.79(m, 1H), 3.66-3.54 (m, 2H), 3.32 (m, 1H), 2.74 (m, 1H), 2.56-2.34 (m,8H), 2.24 (m, 1H), 2.08-1.90 (m, 2H), 1.84-1.62 (m, 7H), 1.44-1.12 (m,3H), 1.05-0.82 (m, 2H).

EXAMPLE 83(1)(3S)-1-(2-butynyl)-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 83, using(2S,3S)-2-(t-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoic acidinstead of(2R,3R)-2-(t-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoic acid,the title compound having the following physical data was obtained.

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.60-7.45 (m,5H), 4.44-4.28 (m, 3H), 4.21 (d, J=2.1 Hz, 1H), 4.10-3.94 (m, 2H), 3.79(m, 1H), 3.66-3.54 (m, 2H), 3.32 (m, 1H), 2.74 (m, 1H), 2.56-2.34 (m,8H), 2.24 (m, 1H), 2.08-1.90 (m, 2H), 1.84-1.62 (m, 7H), 1.44-1.12 (m,3H), 1.05-0.82 (m, 2H).

EXAMPLE 84(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-(4-phenyloxyphenyl)ethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

To the PS-TsCl-HL resin (brand name of Argonaut Technologies, catalognumber 800366) (305 mg) was added a solution of2-(4-phenyloxyphenyl)ethylalcohol (112 mg) in dichloromethane (2 ml) andpyridine (2 ml). The reaction mixture was stirred for 5 hours at roomtemperature. The resin was washed with dichloromethane for 3 times,dimethylformamide for 5 times, dimethylformamide:water=3:1 for 5 times,tetrahydrofuran for 3 times, dichloromethane for 3 times andacetonitrile for 3 times. The obtained resin was added a solution of thecompound prepared in Reference example 15(2) (116 mg) in acetonitrile (5ml) and diisopropylethylamine (0.366 ml). The reaction mixture wasstirred for 18 hours at 70° C. After cooling it, the resin was washedwith acetonitrile, the obtained washings were concentrated. The obtainedresidue was purified by column chromatography on silica gel (ethylacetate:methanol=20:1), and the obtained compound was treated withhydrochloric acid to give the title compound (82 mg) having thefollowing physical data was obtained.

TLC: Rf 0.54 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.37-7.29 (m,4H), 7.11 (t, J=7.2 Hz, 1H), 6.97-6.95 (m, 4H), 4.06 (d, J=7.5, 4.5 Hz,1H), 3.88-3.77 (m, 2H), 3.65 (m, 2H), 3.46-3.36 (m, 4H), 3.13-3.07 (m,2H), 2.48 (m, 2H), 2.28-2.14 (m, 2H), 1.80-1.21 (m, 15H), 0.98 (t, J=7.0Hz, 3H), 0.99-0.91 (m, 2H).

EXAMPLE 84(1) and 84(2)

By the same procedure as described in Example 84 using the correspondingalcohol derivatives respectively instead of2-(4-phenyloxyphenyl)ethylalcohol, and using the compound prepared inReference example 15(1) instead of the compound prepared in Referenceexample 15(2), the following compounds having the following physicaldata were obtained.

EXAMPLE 84(1)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-phenyloxyphenyl)ethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.37 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.37-7.29 (m,4H), 7.11 (t, J=7.5 Hz, 1H), 6.98-6.95 (m, 4H), 4.03 (d, J=7.5, 4.5 Hz,1H), 3.89-3.77 (m, 2H), 3.64 (m, 2H), 3.42-3.32 (m, 4H), 3.12-3.07 (m,2H), 2.45 (m, 2H), 2.29-2.16 (m, 2H), 1.88-1.36 (m, 7H), 0.98 (t, J=7.0Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 84(2)(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-methoxyphenyl)ethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.37 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.22 (d, J=9.0Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.01 (d, J=7.5, 4.5 Hz, 1H), 3.87-3.77(m, 2H), 3.77 (s, 3H), 3.63 (m, 2H), 3.43-3.32 (m, 4H), 3.03 (m, 2H),2.44 (m, 2H), 2.28-2.15 (m, 2H), 1.85-1.36(m, 7H), 0.97 (t, J=7.5 Hz,3H), 0.95 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 85(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-ethoxycarbonylphenyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

To a solution of the compound prepared in Reference example 15(2) (186mg) in dimethylsulfoxide (3 ml) was added ethyl 4-fluorobenzoate (164mg) and potassium carbonate (141 mg). The reaction mixture was stirredfor 24 hours at 140° C. The reaction mixture was added water andt-butylmethyl ether and extracted. The extract was washed with saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=4:1→3:1), and theobtained compound was treated with 4N hydrogen chloride/ethyl acetate togive the title compound (67 mg) having the following physical data.

TLC: Rf 0.27 (hexane:ethyl acetate=2:1); NMR (CD₃OD):δ 8.13 (d, J=8.7Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 4.37 (q, J=7.2 Hz, 2H), 4.31-4.15 (m,2H), 4.07 (dd, J=7.5, 4.5 Hz, 1H), 3.85-3.75 (m, 2H), 3.47-3.38 (m, 2H),2.67-2.50 (m, 2H), 2.30-2.12 (m, 2H), 1.85-1.46 (m, 10H), 1.44-1.19 (m,5H), 1.38 (t, J=7.2 Hz, 3H), 1.05-0.88 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 16(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

By the same procedure as described in Reference example 13→Referenceexample 14→Example 67 using(3S)-2-(t-butoxycarbonylamino)-3-cyclohexylpropanoic acid instead of(2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, andN-benzyloxycarbonyl-4-piperidone instead of N-benzyl-4-piperidone, thetitle compound having the following physical data was obtained.

TLC: Rf 0.35 (hexane:ethyl acetate=1:1); NMR (CD₃OD):δ 7.39-7.31 (m,5H), 6.48 (brs, 1H), 5.16 (s, 2H), 4.15 (brs, 2H), 4.00 (ddd, J=9.6,4.8, 1.5 Hz, 1H), 3.76-3.16 (m, 4H), 2.02-1.12 (m, 19H), 1.08-0.88 (m,2H), 0.92 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 17(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-4-methyl-9-benzyloxycarbonyl-1,4,9-triazaspiro[5.5]undecane

To a solution of the compound prepared in Reference example 16(1 g) indimethylformamide (20 ml) was added 60% sodium hydride (164 mg) underice bath. The reaction mixture was stirred for 1 hour at roomtemperature. The reaction mixture was added methyl iodide (0.3 ml) underice bath. The reaction mixture was stirred overnight at roomtemperature. The reaction mixture was added ice water and extracted withethyl acetate. The extract was washed with water and saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=2:1) to give the title compound (1g) having the following physical data.

TLC: Rf 0.34 (hexane:ethyl acetate=1:1); NMR (CD₃OD):δ 7.40-7.32 (m,5H), 5.16 (s, 2H), 4.12 (brs, 2H), 3.91 (t, J=5.7 Hz, 1H), 3.88 (brs,1H), 3.49 (m, 1H), 3.35 (m, 1H), 2.92 (s, 3H), 2.90 (m, 1H), 2.04-1.10(m, 19H), 1.04-0.82 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 18(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-4-methyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

To a solution of the compound prepared in Reference example 17(1 g) inmethanol (20 ml) was added 10% palladium on carbon (60 mg). Under anatmosphere of hydrogen, the reaction mixture was stirred for 8 hours atroom temperature. The reaction mixture was filtrated through Celite(brand name) and the filtrate was added 4N hydrogen chloride ethylacetate solution and concentrated to give the title compound (799 mg)having the following physical data.

TLC: Rf 0.28 (chloroform:methanol:acetic acid=90:10:1); NMR (CD₃OD):δ4.05 (dd, J=7.5, 4.2 Hz, 1H), 4.01 (dt, J=4.2, 12.9 Hz, 1H), 3.59 (dt,J=3.3, 12.9 Hz, 1H), 3.51 (m, 1H), 3.40 (brd, J=5.4 Hz, 1H), 3.36 (brd,J=5.4 Hz, 1H), 3.25 (m, 1H), 2.93 (s, 3H), 2.37 (dt, J=5.4, 14.4 Hz,1H), 2.32 (dt, J=5.4, 14.4 Hz, 1H), 2.11 (brd, J=14.4 Hz, 1H), 1.99(brd, J=14.4 Hz, 1H), 1.86-1.14 (m, 15H), 1.07-0.87 (m, 2H), 0.97 (t,J=7.2 Hz, 3H).

EXAMPLE 86(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-4-methyl-9-(4-phenyloxyphenymethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 18 instead of the compound prepared inReference example 15, the title compound having the following physicaldata was obtained.

TLC: Rf 0.32 (ethyl acetate); NMR (CD₃OD):δ7.53 (d, J=8.7 Hz, 2H), 7.39(dd, J=8.7, 7.5 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.09-7.01 (m, 4H), 4.34(s, 2H), 4.05 (m, 1H), 4.04 (dd, J=7.2, 3.9 Hz, 1H), 3.68-3.43 (m, 4H),3.27 (m, 1H), 2.93 (s, 3H), 2.48 (dd, J=14.4, 5.4 Hz, 1H), 2.39 (dd,J=14.4, 5.4 Hz, 1H), 2.16 (brd, J=14.4 Hz, 1H), 2.03 (brd, J=14.4 Hz,1H), 1.86-1.58 (m, 8H), 1.53-1.14 (m, 7H), 1.07-0.86 (m, 2H), 0.95 (t,J=7.5 Hz, 3H).

EXAMPLE 87(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-methylpropanoylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(3) instead of the compound prepared inReference example 15, and using 4-(2-methylpropanoylamino)benzaldehydeinstead of 3-formyl-6-phenyloxypyridine the title compound having thefollowing physical data was obtained.

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (d₆-DMSO):δ 10.6 (s, 1H),10.0 (s, 1H), 8.02 (m, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.52 (d, J=8.7 Hz,2H), 5.24 (s, 1H), 4.22 (s, 2H), 3.96 (m, 1H), 3.70 (m, 1H), 3.66-3.12(m, 6H), 2.68-2.20 (m, 4H), 2.02-1.42 (m, 8H), 1.40-1.00 (m, 6H), 1.10(d, J=6.9 Hz, 6H), 0.98-0.64 (m, 2H), 0.88 (t, J=6.9 Hz, 3H).

EXAMPLE 87(1) TO 87(6)

By the same procedure as described in Example 87 using the correspondingaldehyde derivatives respectively instead of4-(2-methylpropanoylamino)benzaldehyde, the following compounds havingthe following physical data were obtained.

EXAMPLE 87(1)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-methoxyacetylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (d₆-DMSO):δ 10.5 (s, 1H),9.95 (s, 1H), 8.02 (m, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz,2H), 4.26 (s, 2H), 4.02 (s, 2H), 3.96 (m, 1H), 3.80-3.10 (m, 7H), 3.38(s, 3H), 2.60-2.18 (m, 4H), 2.02-1.44 (m, 8H), 1.40-1.00 (m, 6H),0.98-0.64 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 87(2)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-phenylacetylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.27 (chloroform:methanol=10:1); NMR (d₆-DMSO):δ 10.6 (s, 1H),10.4 (s, 1H), 8.01 (m, 1H), 7.67 (d, J=9.0 Hz, 2H), 7.54 (d, J=9.0 Hz,2H), 7.40-7.18 (m, 5H), 4.24 (s, 2H), 3.96 (s, 1H), 3.84-3.10 (m, 8H),2.62-2.18 (m, 4H), 2.04-1.42 (m, 8H), 1.40-1.00 (m, 6H), 0.98-0.64 (m,2H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 87(3)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-(4-fluorophenyl)acetylamino)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.26 (chloroform:methanol=10:1); NMR (d₆-DMSO):δ 10.8 (s, 1H),10.4 (s, 1H), 8.01 (m, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz,2H), 7.37 (dd, J=8.4, 5.4 Hz, 2H), 7.14 (t, J=8.4 Hz, 2H), 4.34-3.10 (m,8H), 4.24 (s, 2H), 3.96 (s, 1H), 2.66-2.18 (m, 4H), 2.02-1.42 (m, 8H),1.40-1.00 (m, 6H), 0.98-0.64 (m, 2H), 0.88 (t, J=6.9 Hz, 3H).

EXAMPLE 87(4)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxycarbonylphenylaminocarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (d₆-DMSO):δ 10.90 (br.s,1H), 10.70 (s, 1H), 8.05 (m, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.97 (s, 4H),7.83 (d, J=8.4 Hz, 2H), 5.24 (m, 1H), 4.43 (s, 2H), 3.97 (m, 1H),3.90-3.06 (m, 7H), 3.84 (s, 3H), 2.62-2.20 (m, 3H), 2.06-1.42 (m, 8H),1.40-1.02 (m, 6H), 0.98-0.66 (m, 2H), 0.89 (t, J=6.9 Hz, 3H).

EXAMPLE 87(5)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenylmethyloxycarbonyl)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (d₆-DMSO):δ 10.6 (s, 1H),8.03 (d, J=8.7 Hz, 2H), 8.02 (m, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.42 (d,J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 5.30 (s, 2H), 5.24 (m, 1H), 4.42(s, 2H), 3.96 (m, 1H), 3.86-3.10 (m, 7H), 3.76 (s, 3H), 2.64-2.20 (m,3H), 2.02-1.42 (m, 8H), 1.40-1.00 (m, 6H), 0.96-0.68 (m, 2H), 0.88 (t,J=6.3 Hz, 3H).

EXAMPLE 87(6)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(2-(4-methylaminocarbonylphenyloxy)pyridin-5-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.37 (chloroform:methanol=9:1); NMR (CD₃OD):δ 8.35 (d, J=2.5 Hz,1H), 8.15 (dd, J=8.5, 2.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.23 (d,J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 1H), 4.39 (s, 2H), 4.15 (d, J=2.0 Hz,1H), 4.00 (m, 1H), 3.75 (m, 1H), 3.57-3.45 (m, 3H), 3.30-3.22 (m, 2H),2.92 (s, 3H), 2.56 (m, 1H), 2.50-2.39 (m, 2H), 2.14-1.91 (m, 3H),1.80-1.60 (m, 5H), 1.50-1.10 (m, 6H), 1.00-0.87 (m, 2H), 0.95 (t, J=7.0Hz, 3H).

EXAMPLE 88(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 15(9) instead of the compound prepared inReference example 15, using 4-(4-carboxyphenyloxy)benzaldehyde insteadof 3-formyl-6-phenyloxypyridine, the title compound having the followingphysical data was obtained.

TLC: Rf 0.45 (chloroform:methanol=5:1); NMR (d₆-DMSO):δ 10.4 (s, 1H),8.05 (m, 1H), 7.97 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.19 (d,J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 5.28 (d, J=6.9 Hz, 1H) 4.35 (s,2H), 3.97 (m, 1H), 3.88-3.12 (m, 7H), 2.64-2.20 (m, 3H), 2.06-1.42 (m,8H), 1.40-1.00 (m, 6H), 0.89 (t, J=6.9 Hz, 3H), 0.80 (m, 2H).

EXAMPLE 89(3S)-1-butyl-2,5-dioxo-3-(pyridin-3-ylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Reference example 13→Referenceexample 14→Example 67 using N-t-butoxycarbonyl-3-pyridyl-L-alanineinstead of (2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoicacid, and using N-benzyl-4-piperidone-2-morpholinoethylisonitrileinstead ofN-(4-(4-methylaminocarobonylphenyloxy)phenylmethyl)-4-piperidone thetitle compound having the following physical data was obtained.

TLC: Rf 0.25 (chloroform:methanol=10:1); NMR (CD₃OD):δ 8.82-8.76 (m,2H), 8.55 (d, J=8.4 Hz, 1H), 8.06 (dd, J=7.8, 5.7 Hz, 1H), 7.84 (d,J=9.0 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 7.15-7.02 (m, 4H), 4.55 (t, J=5.4Hz, 1H), 4.33 (s, 2H), 3.80 (m, 1H), 3.68-3.28 (m, 7H), 2.91 (s, 3H),2.56-2.40 (m, 2H), 2.20 (m, 1H), 1.70 (m, 1H), 1.50-1.20 (m, 4H), 0.92(t, J=6.9 Hz, 3H).

EXAMPLE 89(1) TO 89(5)

By the same procedure as described in Example 89 using the correspondingamino acid derivatives respectively instead ofN-t-butoxycarbonyl-3-pyridyl-L-alanine, the following compounds havingthe following physical data were obtained.

EXAMPLE 89(1)(3S)-1-butyl-2,5-dioxo-3-phenylmethyl-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.51 (chloroform:methanol:acetic acid=20:2:1); NMR (CD₃OD):δ7.84 (d, J=9.0 Hz, 2H), 7.56 (d, J=9.0 Hz, 2H), 7.30-7.04 (m, 9H), 4.36(dd, J=4.5, 3.6 Hz, 1H), 4.25 (s, 2H), 3.78 (m, 1H), 3.50-3.02 (m, 6H),3.00-2.84 (m, 4H), 2.38 (m, 1H), 2.02 (m, 1H), 1.86 (m, 1H), 1.60-1.24(m, 4H), 0.93 (t, J=6.9 Hz, 3H), 0.04 (m, 1H).

EXAMPLE 89(2)(3S)-1-butyl-2,5-dioxo-3-(pyridin-2-ylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.46 (chloroform:methanol:acetic acid=20:2:1); NMR (CD₃OD):δ8.78 (dd, J=7.5, 1.5 Hz, 1H), 8.57 (td, J=7.8, 1.5 Hz, 1H), 8.06 (d,J=8.4 Hz, 1H), 8.00 (m, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.64 (d, J=6.6 Hz,2H), 7.16-7.04 (m, 4H), 4.68 (dd, J=6.9, 5.7 Hz, 1H), 4.38 (s, 2H), 3.84(m, 1H), 3.70-3.32 (m, 7H), 2.91 (s, 3H), 2.64-2.44 (m, 2H), 2.16 (m,1H), 2.06 (m, 1H), 1.50-1.22 (m, 4H), 0.91 (t, J=6.9 Hz, 3H).

EXAMPLE 89(3)(3S)-1-butyl-2,5-dioxo-3-hydroxymethyl-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol:acetic acid=20:2:1); NMR (CD₃OD):δ7.84 (d, J=9.0 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H),7.07 (d, J=9.0 Hz, 2H), 4.36 (s, 2H), 4.02-3.88 (m, 3H), 3.80-3.44 (m,5H), 3.30 (m, 1H), 2.91 (s, 3H), 2.60-2.36 (m, 3H), 2.18 (m, 1H), 1.64(m, 1H), 1.50-1.26 (m, 3H), 1.02-0.90 (m, 3H).

EXAMPLE 89(4)(3S)-1-butyl-2,5-dioxo-3-(pyridin-1-oxido-2-ylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.86 (chloroform:methanol:acetic acid=10:2:1); NMR (CD₃OD):δ8.70 (dd, J=5.4, 1.0 Hz, 1H), 8.05 (td, J=6.6, 1.2 Hz, 1H), 7.92-7.72(m, 4H), 7.64 (d, J=9.0 Hz, 2H), 7.20-7.06 (m, 4H), 4.67 (d, J=6.3 Hz,1H), 4.36 (s, 2H), 3.86-3.18 (m, 8H), 2.91 (s, 3H), 2.70-2.26 (m, 2H),2.34-2.06 (m, 2H), 1.60-1.44 (m, 2H), 1.44-1.24 (m, 2H), 0.92 (t, J=7.5Hz, 3H).

EXAMPLE 89(5)(3S)-1-butyl-2,5-dioxo-3-(pyridin-1-oxido-3-ylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.65 (chloroform:methanol:acetic acid 10:2:1); NMR (CD₃OD):δ8.74-8.60 (m, 2H), 8.06 (d, J=7.8 Hz, 1H), 7.88 (m, 1H), 7.84 (d, J=8.7Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7Hz, 2H), 4.52 (t, J=5.1 Hz, 1H), 4.33 (s, 2H), 4.00 (m, 1H), 3.78 (m,1H), 3.60 (m, 1H), 3.56-3.18 (m, 5H), 2.91 (s, 3H), 2.56-2.18 (m, 2H),2.20 (m, 1H), 1.66 (m, 1H), 1.52-1.22 (m, 4H), 0.93 (t, J=6.9 Hz, 3H).

EXAMPLE 90(3R)-1-(4-methoxyphenylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Reference example 13→Referenceexample 14→Example 67 using(2R,3R)-2-(t-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoic acidinstead of (2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoicacid, and using 4-methoxybenzylamine instead of n-butylamine, usingN-(4-(4-methylaminocarobonylphenyloxy)phenylmethyl)-4-piperidone insteadof N-benzyl-4-piperidone, using 2-morpholinoethylisonitrile instead ofbenzylisonitrile, the title compound having the following physical datawas obtained.

TLC: Rf 0.24 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.84 (d, J=8.7Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.7Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 4.48 (m, 1H),4.33 (s, 4H), 3.96 (m, 1H), 3.75 (m, 1H), 3.75 (s, 3H), 3.58-3.18 (m,3H), 2.92 (s, 3H), 2.66-2.28 (m, 3H), 2.16-1.58 (m, 7H), 1.40-0.82 (m,5H).

EXAMPLE 90(1) TO 90(4)

By the same procedure as described in Example 90 using the correspondingamines instead of 4-methoxybenzylamine, the title compounds wereobtained.

EXAMPLE 90(1)(3R)-1-phenylmethyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.28 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.85 (d, J=8.7Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.40-7.02 (m, 5H), 7.13 (d, J=8.7 Hz,2H), 7.06 (d, J=8.7 Hz, 2H), 4.58 (m, 1H), 4.33 (s, 4H), 3.96 (m, 1H),3.76 (m, 1H), 3.54-3.18 (m, 3H), 2.92 (s, 3H), 2.64-2.28 (m, 3H),2.14-1.58 (m, 7H), 1.40-0.80 (m, 5H).

EXAMPLE 90(2)(3R)-1-(2-methoxyethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

TLC: Rf 0.35 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.84 (d, J=8.7Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.36 (s, 2H), 4.18 (d, J=2.1 Hz, 1H), 3.98 (m, 1H), 3.86-3.18(m, 8H), 3.31 (s, 3H), 2.91 (s, 3H), 2.60-1.58 (m, 10H), 1.42-0.80 (m,5H).

EXAMPLE 90(3)(3R)-1-(pyridin-2-ylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.83 (chloroform:methanol:acetic acid=10:2:1); NMR (CD₃OD):δ8.76 (dd, J=6.6, 1.8 Hz, 1H), 8.54 (td, J=8.4, 1.8 Hz, 1H), 8.12 (d,J=8.4 Hz, 1H), 7.93 (dd, J=8.4, 6.6 Hz, 1H), 7.83 (d, J=9.0 Hz, 2H),7.65 (d, J=8.7 Hz, 2H), 7.14-7.02 (m, 4H), 5.34-5.20 (m, 2H), 4.38 (s,2H), 4.30 (d, J=1.8 Hz, 1H), 3.96 (m, 1H), 3.78 (m, 1H), 3.52-3.38 (m,2H), 3.32 (m, 1H), 2.90 (s, 3H), 2.72-2.54 (m, 3H), 2.30 (m, 1H), 2.06(m, 1H), 1.88 (m, 1H), 1.82-1.50 (m, 4H), 1.28-1.06 (m, 3H), 1.06-0.80(m, 2H).

EXAMPLE 90(4)(3R)-1-(pyridin-3-ylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

TLC: Rf 0.58 (chloroform:methanol:acetic acid=10:2:1); NMR (CD₃OD):δ8.89 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.64 (d, J=8.1 Hz, 1H), 8.03 (dd,J=8.1, 5.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H),7.18-7.02 (m, 4H), 5.19 (d, J=18.0 Hz, 1H), 5.11 (d, J=18.0 Hz, 1H),4.40-4.26 (m, 3H), 3.90 (m, 1H), 3.78 (m, 1H), 3.50-3.38 (m, 2H), 3.30(m, 1H), 2.90 (s, 3H), 2.74-2.42 (m, 3H), 2.20-1.88 (m, 3H), 1.82-1.56(m, 4H), 1.32-1.06 (m, 3H), 1.02-0.80 (m, 2H).

REFERENCE EXAMPLE 19(3R)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Reference example 13→Referenceexample 14→Example 67→Reference example 15 usingN-t-butoxycarbonyl-D-cyclohexylalanine instead of(2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, thetitle compound having the following physical data was obtained.

TLC: Rf 0.59 (n-butanol:acetic acid:H₂O=4:2:1); NMR (CD₃OD):δ 4.05 (dd,J=7.5, 4.8 Hz, 1H), 3.83-3.69 (m, 2H), 3.42-3.37 (m, 4H), 2.39-2.07 (m,4H), 1.80-1.49 (m, 10H), 1.45-1.19 (m, 5H), 1.03-0.91 (m, 5H); Opticalrotation: [α]_(D)+35.5 (c 1.05, methanol, 21° C.).

EXAMPLE 91(3R)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 19 instead of the compound prepared inReference example 15, and using 4-(4-carboxyphenyloxy)benzaldehydeinstead of 3-formyl-6-phenyloxypyridine, the title compound having thefollowing physical data was obtained.

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR (d₆-DMSO):δ 10.92 (br-s,1H), 8.41 (br-s, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H),7.17 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 4.32 (s, 2H), 3.91 (m,1H), 3.59-3.35 (m, 6H), 2.56-2.35 (m, 2H), 2.10 (m, 1H), 1.98 (m, 1H),1.72-1.35 (m, 10H), 1.32-1.14 (m, 5H), 0.90-0.78 (m, 5H).

EXAMPLE 92(3S)-1-butyl-2,5-dioxo-3-(pyridin-1-oxido-2-ylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.9-oxide

To a solution of the free form of the compound prepared in Example 89(2)(117 mg) in chloroform (10 ml) was added dropwise the solution (4 ml) of3-chloroperbenzoic acid (114 mg). After the reaction mixture was stirredovernight at room temperature, the solvent was evaporated. The obtainedresidue was purified by column chromatography on silica gel (FujiSilysia Chemical Ltd., N H-DM1020, chloroform) to give the titlecompound (100 mg) having the following physical data.

TLC: Rf 0.23 (chloroform:methanol:acetic acid=20:2:1); NMR (CDCl₃):δ8.81 (s, 1H), 8.28 (dd, J=6.0, 1.2 Hz, 1H), 7.77 (d, J=8.7 Hz, 2H),7.52-7.46 (m, 3H), 7.32-7.22 (m, 2H), 7.16-6.98 (m, 4H), 6.32 (m, 1H),4.40-4.24 (m, 4H), 3.87 (dd, J=11.0, 5.1 Hz, 1H), 3.66-3.34 (m, 4H),3.16-2.86 (m, 4H), 3.01 (d, J=4.5 Hz, 3H), 1.84-1.20 (m, 6H), 0.90 (t,J=7.2 Hz, 3H).

REFERENCE EXAMPLE 201-butyl-2,5-dioxo-3-(morpholin-4-ylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Reference example 13→Referenceexample 14→Example 67→Reference example 15 using2-(t-butoxycarbonylamino)-3-(morpholin-4-yl)propanoic acid instead of(2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, thetitle compound having the following physical data was obtained.

TLC: Rf 0.07 (chloroform:methanol=10:1); NMR (CD₃OD):δ 4.76 (dd, J=8.4,4.8 Hz, 1H), 4.05-3.82 (m, 6H), 3.71-3.40 (m, 10H), 2.41 (m, 1H),2.31-2.21 (m, 3H), 1.98-1.54 (m, 2H), 1.46-1.36 (m, 2H), 0.97 (t, J=7.5Hz, 3H).

EXAMPLE 931-butyl-2,5-dioxo-3-(morpholin-4-ylmethyl)9-(4-(4-methylaminocarbonylphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.2hydrochloride

By the same procedure as described in Example 68 using the compoundprepared in Reference example 20 instead of the compound prepared inReference example 15, and using4-(4-methylaminocarobonyl)phenyloxybenzaldehyde instead of3-formyl-6-phenyloxypyridine, the title compound having the followingphysical data was obtained.

TLC: Rf 0.41 (chloroform:methanol=10:1); NMR (CD₃OD):δ 7.84 (d, J=9.0Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 7.07 (d, J=9.0Hz, 2H), 4.73 (dd, J=8.1, 5.1 Hz, 1H), 4.37 (s, 2H), 4.10-3.85 (m, 5H),3.76-3.43 (m, 9H), 3.40-3.20 (m, 2H), 2.91 (s, 3H), 2.63-2.43 (m, 2H),2.33-2.24 (m, 2H), 1.65-1.50 (m, 2H), 1.44-1.34 (m, 2H), 0.96 (t, J=7.0Hz, 3H).

EXAMPLE 94(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(N-hydroxycarbamoyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

To a suspension of the compound prepared in Example 75(54) (120 mg) and(1-methoxyisopropyl)oxyamine (31 mg) in dimethylformamide (1.6 ml) wasadded diisopropylethylamine (68 μl),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.hydrochloride (56 mg)and 1-hydroxybenztriazole (40 mg). The reaction mixture was stirred for1 hour at room temperature. The reaction mixture was added 1Nhydrochloric acid (2 ml) and stirred for 15 minutes at room temperature.The reaction mixture was diluted with water and extracted with ethylacetate. The extract was washed with water, saturated aqueous solutionof sodium bicarbonate and saturated aqueous solution of sodium chlorideand the obtained residue was dried over anhydrous sodium sulfate andconcentrated. To a solution of the obtained residue in methanol wasadded 4N hydrogen chloride/ethyl acetate solution and concentrated. Theobtained residue was washed with ethyl acetate to give the titlecompound (116 mg) having the following physical data.

TLC: Rf 0.43 (chloroform:methanol:acetic acid=20:4:1); NMR (CD₃OD):δ7.79 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H),7.06 (d, J=8.7 Hz, 2H), 4.36 (s, 2H), 4.15 (d, J=2.1 Hz, 1H), 4.00 (m,1H), 3.75 (m, 1H), 3.60-3.40 (m, 3H), 3.30-3.11 (m, 2H), 2.58-2.27 (m,3H), 2.19-1.96 (m, 3H), 1.93-1.60 (m, 5H), 1.50-1.09 (m, 6H), 1.05-0.80(m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 95(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenylcarbonyl)-1,4,9-triazaspiro[5.5]undecane

To a solution of 4-(4-methylaminocarobonylphenyloxy)benzoic acid (53.8mg) in dimethylformamide (4 ml) was added 1-hydroxybenztriazole (34.9mg) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide-hydrochloride(49.5 mg). The reaction mixture was stirred for 40 minutes at roomtemperature. The reaction mixture was added the compound prepared inExample 69(3) (100 mg) and stirred for 19 hours at room temperature. Thereaction mixture was diluted with methylene dichloride, added water, andextracted with methylene dichloride. The extract was washed with 10%aqueous solution of citric acid and saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and concentrated. Theobtained residue was purified by column chromatography on silica gel(ethyl acetate:methanol=10:1) and washed with diethyl ether to give thetitle compound (56.1 mg) having the following physical data.

TLC: Rf 0.41 (ethyl acetate:methanol=10:1); NMR (CD₃OD):δ 7.84 (d, J=8.7Hz, 2H), 7.49 (t, J=8.7 Hz, 2H), 7.13-7.06 (m, 4H), 3.70 (m, 1H), 4.16(m, 1H), 4.12-2.98 (m, 6H), 2.91 (s, 3H), 2.42-0.80 (m, 19H), 0.96 (t,J=6.9 Hz, 3H).

EXAMPLE 96(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonylphenyloxy)phenyl)-1,4,9-triazaspiro[5.5]undecane.hydrochloride

By the same procedure as described in Reference example 13→Referenceexample 14→Example 67 using(2R,3R)-2-(t-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoic acidinstead of (2R,3R)-2-(t-butoxycarbonylamino)-3-hydroxy-4-methylpentanoicacid, and usingN-(4-(4-methylaminocarobonylphenyloxy)phenyl)-4-piperidone instead ofN-benzyl-4-piperidone, and using 2-morpholinoethylisonitrile instead ofbenzylisonitrile, the title compound having the following physical datawas obtained.

TLC: Rf 0.40 (ethyl acetate); NMR (CD₃OD):δ 7.87 (d, J=9.0 Hz, 2H), 7.78(d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 4.65(m, 1H), 4.39 (m, 1H), 4.20 (d, J=1.8 Hz, 1H), 3.73-3.65 (m, 3H),3.43-3.27 (m, 2H), 2.91 (s, 3H), 2.90-2.52 (m, 3H), 2.25 (m, 1H),2.10-1.90 (m, 2H), 1.85-1.60 (m, 5H), 1.60-1.10 (m, 6H), 0.99 (t, J=7.2Hz, 3H), 1.00-0.82 (m, 2H).

EXAMPLE 97 Inhibiting Activity to HIV-1 Infection to Human PBMC

Human PBMC (peripheral blood mononuclear cell) was isolated fromHIV-negative healthy persons by a Ficol-Hipaque density-gradientcentrifugation and incubated for 3 days in the presence of 10 μg/ml PHA(phytohemagglutinin). PHA-stimulated PBMC was suspended in RPMI 1640containing 10% serum to give a density of 1×10⁵ cells/ml and poured intoa 96-well microplate. Furthermore, in the presence of a sole testcompound in various concentrations or in the co-presence with otheranti-HIV inhibitor (such as AZT (zidovudin) or AMD 3100), various HIV-1cell lines of 50 TCID₅₀ (such as HIV-1_(LAI), HIV-1_(NL4-3),HIV-1_(BaL), HIV-1_(JRFL), HIV-1_(89.6), HIV-1 HIV-1_(ERS104pre),HIV-1_(JSL), HIV-1_(MM), HIV-1_(TM) and HIV-1_(MOKW)) were exposed.After being incubated for 7 days, the amount of HIV-1p24 antigen on thesupernatant liquid of the incubation was measured by an EIA method usingLumipulse F (Fuji Rebio).

Inhibiting effect to HIV-1 infection to human PBMC was investigated bythe joint use of the compound of Example 2(1) with AMD 3100. Thecompound of Example 2(1) in various concentrations and AMD 3100 wereadded either solely or combinably and an assay was carried out. Resultsof the compound of Example 2(1) to HIV-1_(89.6) and to a mixed virus ofHIV-1_(BaL) and HIV-1_(NL4-3) are shown in Tables 1 and 2. Inhibitingeffects of both compounds when the p24 amount where the compounds arenot added is defined as 100% are shown in terms of % control.

TABLE 1 Inhibiting Effect of Combination of Compound of Example 2(1)with AMD 3100 to HIV-1_(89.6) Compound of Example 2(1) (μM) 0 0.1 1 AMD3100 0 100 72.0 64.5 0.01 58.3 38.0 15.1 0.1 6.9 6.0 0.7 % control

TABLE 2 Inhibiting Effect of Combination of Compound of Example 2(1)with AMD 3100 to Mixed Virus of HIV-1_(BaL) and HIV-1_(NL4-3) (1:1)Compound of Example 2(1) (μM) 0 0.1 1 AMD 3100 0 100 63.8 52.4 0.01 59.132.1 10.5 0.1 44.2 17.8 1.5 % control

Inhibiting effect of the compound of Example 2(1) to human PBMC infectedby wild-type HIV-1 (HIV-1_(MOKW)) and by multidrug resistant HIV-1(HIV-1_(JSL) and HIV-1_(MM)) to reverse transcriptase inhibitor andprotease inhibitor was investigated. Inhibiting effect (IC₅₀ values) ofthe compound of Example 2(1) to various kinds of viruses is shown inTable 3.

TABLE 3 Inhibiting Effect to Infection of Multidrug Resistant HIV-1Strains (HIV-1_(JSL) and HIV-1_(MM)) to Reverse Transcriptase Inhibitorand Protease Inhibitor to Human PBMC IC₅₀ (μM) Wild-Type HIV MultidrugResistant HIV-1 HIV-1_(MOKW) HIV-1_(JSL) HIV-1_(MM) Compound of 0.040 ±0.029 0.064 ± 0.011 0.048 ± 0.062 Ex. 2(1)

Inhibiting effect to human PBMC infected by HIV-1 HIV-1_(BaL) by thejoint use of the compound of Example 2(1) and saquinavir (SQV) which isan anti-HIV inhibitor was investigated. The effects of the compound ofExample 2(1) and saquinavir (SQV) used either solely or combinably areshown in Table 4. Inhibiting effects of both compounds when the p24amount where the compounds are not added is defined as 100% are shown interms of % control.

TABLE 4 Inhibiting Effect by Combination of Compound of Example 2(1)with Saquinavir to HIV-1_(BaL) Infected to Human PBMC Compound ofExample 2(1) (μM) 0 0.1 Saquinavir 0 100 75.4 0.01 53.8 44.3 % control

Inhibiting effect to human PBMC infected by HIV-1 HIV-1BaL by the jointuse of the compound of Example 75(54) and saquinavir (SQV) which is ananti-HIV inhibitor 10 was investigated. The effects of the compound ofExample 75(54) and saquinavir (SQV) used either solely or combinably areshown in Table 5. Inhibiting effects of both compounds when the p24amount where the compounds are not added is defined as 100% are shown interms of % control.

TABLE 5 Inhibiting Effect by Combination of Compound of Example 75(54)with Saquinavir to HIV-1_(BaL) Infected to Human PBMC Compound ofExample 75(54) (nM) 0 0.2 1 5 Saquinavir 0 100 64.2 34.2 10.6 1 78.166.0 32.8 10.8 5 67.7 52.0 29.3 6.1 25 5.9 5.7 3.8 1.6 % control

FORMULATION EXAMPLE 1

The following components were admixed in a conventional manner, punchedout to give 100 tablets each containing 50 mg of active ingredient.

9-(1,4-benzodioxan-6-ylmethyl)-1-butyl-3-cyclohexylmethyl-2,5- 5.0 gdioxo-1,4,9-triazaspiro[5.5]undecane.hydrochloride calcium carboxymethylcellulose (disintegrant) 0.2 g magnesium stearate (lubricant) 0.1 gmicrocrystalline cellulose 4.7 g

FORMULATION EXAMPLE 2

The following components were admixed in a conventional technique. Thesolution was sterilized in a conventional technique, filled in ampoules5 ml each and freeze-dried over in a conventional technique to give 100ampoules each containing 20 mg of active ingredient.

9-(1,4-benzodioxan-6-ylmethyl)-1-butyl-3-cyclohexylmethyl- 2.0 g2,5-dioxo-1,4,9-triazaspiro[5.5]undecane.hydrochloride mannitol 20 gdistilled water 500 mL

1. A method for treatment of a disease selected from the groupconsisting of HIV infection, AIDS, and HIV infection acquiring multidrugresistance, which comprises administering to a subject in need thereofan effective amount of a triazaspiro[5.5]undecane compound representedby formula (I):

wherein R¹ is (1) hydrogen, (2) C1-18 alkyl, (3) C2-18 alkenyl, (4)C2-18 alkynyl, (5) —COR⁶, (6) —CONR⁷R⁸, (7) —COOR⁹, (8) —SO₂R¹⁰, (9)—COCOOR¹¹, (10) —CONR¹²COR¹³, (11) Cyc1 or (12) C1-18 alkyl, C2-18alkenyl or C2-18 alkynyl substituted by 1-5 substituents selected fromthe group consisting of (a) halogen, (b) —CONR⁷R⁸, (c) —COOR⁹, (d)—OR¹⁴, (e) —SR¹⁵, (f) —NR¹⁶R¹⁷, (g) —NR¹⁸COR¹⁹, (h) —SO₂NR²⁰R²¹, (i)—OCOR²², (j) —NR²³SO₂R²⁴, (k) —NR²⁵COOR²⁶, (l) —NR²⁷CONR²⁸R²⁹, (m) Cyc1,(n) keto and (o) —N(SO₂R²⁴)₂, R⁶-R⁹, R¹¹-R²¹, R²³, R²⁵ and R²⁷-R²⁹ areeach independently (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4)C2-8 alkynyl, (5) Cyc1 or (6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted by 1-5 substituents selected from the group consisting of(a) Cyc1, (b) halogen, (c) —OR³⁰, (d) —SR³¹, (e) —NR³²R³³, (f) —COOR³⁴,(g) —CONR³⁵R³⁶ (h) —NR³⁷COR³⁸, (i) —NR³⁹SO₂R⁴⁰ and (j) —N(SO₂R⁴⁰)₂, R⁷and R⁸, R²⁰ and R²¹, or R²⁸ and R²⁹, taken together, are 1) C2-6alkylene, 2) —(C2-6 alkylene)-O—(C2-6 alkylene)-, 3) —(C2-6alkylene)-S—(C2-6 alkylene)- or 4) —(C2-6 alkylene)-NR¹⁹⁵—(C2-6alkylene)-, wherein R¹⁹⁵ is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkylsubstituted by phenyl, R¹⁰, R²², R²⁴ and R²⁶ are each independently (1)C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) Cyc1 or (5) C1-8alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituentsselected from the group consisting of (a) Cyc1, (b) halogen, (c) —OR³⁰,(d) —SR³¹, (e) —NR³²R³³, (f) —COOR³⁴, (g) —CONR³⁵R³⁶, (h) —NR³⁷COR³⁸,(i) —NR³⁹SO₂R⁴⁰ and (j) —N(SO₂R⁴⁰)₂, R³⁰-R³⁷ and R³⁹ are eachindependently hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted byCyc1, R³⁵ and R³⁶, taken together, are 1) C2-6 alkylene, 2) —(C2-6alkylene)-O—(C2-6 alkylene)-, 3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or4) —(C2-6 alkylene)-NR¹⁹⁶—(C2-6 alkylene)- wherein R¹⁹⁶ is hydrogen,C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl, R³⁸ and R⁴⁰ areeach independently C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1,Cyc1 is C3-15 mono-, bi- or tri-(fused or spiro)carbocyclic ring or 3-15membered mono-, bi- or tri-(fused or spiro)cyclic hetero ring containing1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulfur atoms, whereinCyc1 may be substituted by 1-5 of R⁵¹, R⁵¹ is (1) C1-8 alkyl, (2) C2-8alkenyl, (3) C2-8 alkynyl, (4) halogen, (5) nitro, (6) trifluoromethyl,(7) trifluoromethoxy, (8) nitrile, (9) keto, (10) Cyc2, (11) —OR⁵², (12)—SR⁵³ (13) —NR⁵⁴R⁵⁵, (14) —COOR⁵⁶, (15) —CONR⁵⁷R⁵⁸, (16) —NR⁵⁹COR⁶⁰,(17) —SO₂NR⁶¹R⁶², (18) —OCOR⁶³, (19) —NR⁶⁴SO₂R⁶⁵, (20) —NR⁶⁶COOR⁶⁷, (21)—NR⁶⁸CONR⁶⁹R⁷⁰, (22) —B(OR⁷¹)₂, (23) —SO₂R⁷², (24) —N(SO₂R⁷²)₂, (25)—S(O)R⁷² or (26) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by1-5 substituents selected from the group consisting of (a) halogen, (b)Cyc2, (c) —OR⁵², (d) —SR⁵³, (e) —NR⁵⁴R⁵⁵, (f) —COOR⁵⁶, (g) —CONR⁵⁷R⁵⁸,(h) —NR⁵⁹COR⁶⁰, (i) —SO₂NR⁶¹R⁶², (j) —OCOR⁶³, (k) —NR⁶⁴SO₂R⁶⁵, (l)—NR⁶⁶COOR⁶⁷, (m) —R⁶⁸CONR⁶⁹R⁷⁰, (n) —B(OR⁷¹)₂, (o) —SO₂R⁷², (p)—N(SO₂R⁷²)₂, (q) —S(O)R⁷² and (r) keto, R⁵²-R⁶², R⁶⁴, R⁶⁶ and R⁶⁸-R⁷¹are each independently 1) hydrogen, 2) C1-8 alkyl, 3) C2-8 alkenyl, 4)C2-8 alkynyl, 5) Cyc2 or 6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted by Cyc2, —OR⁷³, —COOR⁷⁴ or —NR⁷⁵R⁷⁶, R⁵⁷ and R⁵⁸, R⁶¹ andR⁶² or R⁶⁹ and R⁷⁰ taken together, are 1) C2-6 alkylene, 2) —(C2-6alkylene)-O—(C2-6 alkylene)-, 3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or4) —(C2-6 alkylene)-NR¹⁹⁷—(C2-6 alkylene)-, wherein R¹⁹⁷ is hydrogen,C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl, R⁶³, R⁶⁵, R⁶⁷and R⁷² are each independently 1) C1-8 alkyl, 2) C2-8 alkenyl, 3) C2-8alkynyl, 4) Cyc2 or 5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted by Cyc2, —OR⁷³, —COOR⁷⁴ or —NR⁷⁵R⁷⁶, R⁷³-R⁷⁶ are eachindependently hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted byCyc2, Cyc2 has the same meaning as Cyc1, wherein Cyc2 may be substitutedby 1-5 of R⁷⁷, R⁷⁷ is 1) C1-8 alkyl, 2) halogen, 3) nitro, 4)trifluoromethyl, 5) trifluoromethoxy, 6) nitrile, 7) —OR⁷⁸, 8) —NR⁷⁹R⁸⁰,9) —COOR⁸¹, 10) —SR⁸², 11) —CONR⁸³R⁸⁴, 12) C2-8 alkenyl, 13) C2-8alkynyl, 14) keto, 15) Cyc6, 16) —NR¹⁶¹COR¹⁶², 17) —SO₂NR⁶³R¹⁶⁴, 18)—OCOR¹⁶⁵, 19) —NR¹⁶⁶SO₂R¹⁶⁷, 20) —NR¹⁶⁸COOR¹⁶⁹, 21) —NR¹⁷⁰CONR¹⁷¹R¹⁷²,22) —SO₂R¹⁷³, 23) —N(SO₂R¹⁶⁷)₂, 24) —S(O)R¹⁷³ or 25) C1-8 alkyl, C2-8alkenyl or C2-8 alkynyl substituted by 1-5 substituents selected fromthe group consisting of (a) halogen, (b) —OR⁷⁸, (c) —NR⁷⁹R⁸⁰, (d)—COOR⁸¹, (e) —SR⁸², (f) —CONR⁸³R⁸⁴, (g) keto, (h) Cyc6, (i) —N¹⁶¹COR¹⁶²,(j) —SO₂NR¹⁶³R¹⁶⁴, (k) —OCOR¹⁶⁵, (l) —NR¹⁶⁶SO₂R¹⁶⁷, (m) —NR¹⁶⁸COOR¹⁶⁹,(n) —NR¹⁷⁰CONR¹⁷¹R¹⁷², (o) —SO₂R¹⁷³, (p) —N(SO₂R¹⁶⁷)₂ and (q) —S(O)R¹⁷³,R⁷⁸-R⁸⁴, R¹⁶¹-R¹⁶⁴, R¹⁶⁶, R¹⁶⁸ and R¹⁷⁰-R¹⁷² are each independently, (a)hydrogen, (b) C1-8 alkyl, (c) C2-8 alkenyl, (d) C2-8 alkynyl, (e) Cyc6,(f) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc6,—OR¹⁷⁴, —COOR¹⁷⁵, —NR¹⁷⁶R¹⁷⁷ or —CONR¹⁷⁸R¹⁷⁹, R⁸³ and R⁸⁴, R¹⁶³ andR¹⁶⁴, or R¹⁷¹ and R¹⁷², taken together, are 1) C2-6 alkylene, 2) —(C2-6alkylene)-O—(C2-6 alkylene)-, 3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or4) —(C2-6 alkylene)-NR¹⁹⁸—(C2-6 alkylene)-, wherein R¹⁹⁸ is hydrogen,C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl, R¹⁶⁵, R¹⁶⁷, R¹⁶⁹and R¹⁷³ are each independently (a) C1-8 alkyl, (b) C2-8 alkenyl, (c)C2-8 alkynyl, (d) Cyc6 or (e) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted by Cyc6, —OR¹⁷⁴, —COOR¹⁷⁵, —NR¹⁷⁶R¹⁷⁷ or —CONR¹⁷⁸R¹⁷⁹,R¹⁷⁴-R¹⁷⁷ are each independently 1) hydrogen, 2) C1-8 alkyl, 3) Cyc6 or4) C1-8 alkyl substituted by Cyc6, R¹⁷⁸ and R¹⁷⁹, taken together, are 1)C2-6 alkylene, 2) —(C2-6 alkylene)-O—(C2-6 alkylene)-, 3) —(C2-6alkylene)-S—(C2-6 alkylene)- or 4) —(C2-6 alkylene)-NR¹⁹⁹—(C2-6alkylene)-, wherein R¹⁹⁹ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkylsubstituted by phenyl, Cyc6 is C3-8 mono-carbocyclic ring or 3-8membered mono-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2oxygen atoms and/or 1-2 sulfur atoms, wherein Cyc6 may be substituted by1-5 of R¹⁸⁰, R¹⁸⁰ is (1) C1-8 alkyl, (2) halogen, (3) nitro, (4)trifluoromethyl, (5) trifluoromethoxy, (6) nitrile, (7) —OR¹⁸¹, (8)—NR¹⁸²R¹⁸³, (9) —COOR¹⁸⁴, (10) —SR¹⁸⁵ or (11) —CONR¹⁸⁶R¹⁸⁷, R¹⁸¹-R¹⁸⁷are each independently 1) hydrogen, 2) C1-8 alkyl, 3) phenyl or 4) C1-8alkyl substituted by phenyl, R¹⁸² and R¹⁸³ or R¹⁸⁶ and R¹⁸⁷, takentogether, are 1) C2-6 alkylene, 2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or 4) —(C2-6alkylene)-NR²⁰⁰—(C2-6 alkylene)-, wherein R²⁰⁰ is hydrogen, C1-8 alkyl,phenyl, C1-8 alkyl substituted by phenyl, R² is (1) hydrogen, (2) C1-8alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) —OR⁹⁰, (6) Cyc3 or (7)C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituentsselected from the group consisting of (a) halogen, (b) —OR⁹⁰, (c) —SR⁹¹,(d) —NR⁹²R⁹³, (e) —COOR⁹⁴, (f) —CONR⁹⁵R⁹⁶, (g) —NR⁹⁷R⁹⁸, (h)—SO₂NR⁹⁹R¹⁰⁰, (i) —OCOR¹⁰¹, (j) —NR¹⁰²SO₂R¹⁰³, (k) —NR¹⁰⁴COOR¹⁰⁵, (l)—NR¹⁰⁶CONR¹⁰⁷R¹⁰⁸, (m) Cyc3, (n) keto and (o) —N(SO₂R¹⁰³)₂, R⁹⁰-R¹⁰⁰,R¹⁰², R¹⁰⁴ and R¹⁰⁶-R¹⁰⁸ are each independently 1) hydrogen, 2) C1-8alkyl, 3) C2-8 alkenyl, 4) C2-8 alkynyl, 5) Cyc3 or 6) C1-8 alkyl, C2-8alkenyl or C2-8 alkynyl substituted by Cyc3, R⁹⁵ and R⁹⁶, R⁹⁹ and R¹⁰⁰,or R¹⁰⁷ and R¹⁰⁸, taken together, are 1) C2-6 alkylene, 2) —(C2-6alkylene)-O—(C2-6 alkylene)-, 3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or4) —(C2-6 alkylene)-NR²⁰¹—(C2-6 alkylene)-, R²⁰¹ is hydrogen, C1-8alkyl, phenyl or C1-8 alkyl substituted by phenyl, R¹⁰¹, R¹⁰³ and R¹⁰⁵are each independently 1) C1-8 alkyl, 2) C2-8 alkenyl, 3) C2-8 alkynylor 4) Cyc3, or C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted byCyc3, Cyc3 has the same meaning as Cyc1, wherein Cyc3 may be substitutedby 1-5 of R¹⁰⁹, and R¹⁰⁹ has the same meaning as R⁵¹, R³ and R⁴ are eachindependently (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8alkynyl, (5) —COOR¹²⁰, (6) —CONR¹²¹R¹²², (7) Cyc4 or (8) C1-8 alkyl,C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituents selectedfrom the group consisting of (a) halogen, (b) nitrile, (c) Cyc4, (d)—COOR¹²⁰, (e) —CONR¹²¹R¹²², (f) —OR¹²³, (g) —SR¹²⁴, (h) —NR¹²⁵R¹²⁶, (i)—NR¹²⁷COR¹²⁸, (j) —SO₂NR¹²⁹R¹³⁰, (k) —OCOR¹³¹, (l) —NR¹³²SO₂R¹³³, (m)—NR¹³⁴COOR¹³⁵, (n) —NR¹³⁶CONR¹³⁷R¹³⁸, (o) —S—SR¹³⁹, (p) —NHC(═NH)NHR¹⁴⁰,(q) keto, (r) —NR¹⁴⁵CONR¹⁴⁶COR¹⁴⁷ and (s) —N(SO₂R¹³³)₂, R¹²⁰-R¹³⁰, R¹³²,R¹³⁴, R¹³⁶-R¹³⁸, R¹⁴⁵ and R¹⁴⁶ are each independently 1) hydrogen, 2)C1-8 alkyl, 3) C2-8 alkenyl, 4) C2-8 alkynyl, 5) Cyc4 or 6) C1-8 alkyl,C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4, halogen, —OR¹⁴⁸,—SR¹⁴⁹, —COOR¹⁵⁰ or —NHCOR¹⁴¹, R¹²¹ and R¹²² R¹²⁹ and R¹³⁰, or R¹³⁷ andR¹³⁸, taken together, are 1) C2-6 alkylene, 2) —(C2-6 alkylene)-O—(C2-6alkylene)-, 3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or 4) —(C2-6alkylene)-NR²⁰²—(C2-6 alkylene)-, wherein R²⁰² is hydrogen, C1-8 alkyl,phenyl, C1-8 alkyl substituted by phenyl, R¹³¹, R¹³³, R¹³⁵, R¹³⁹ andR¹⁴⁷ are each independently 1) C1-8 alkyl, 2) C2-8 alkenyl, 3) C2-8alkynyl, 4) Cyc4 or 5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted by Cyc4, halogen, —OR¹⁴⁸, —SR¹⁴⁹, —COOR¹⁵⁰ or —NHCOR¹⁴¹,R¹⁴⁰ is hydrogen, —COOR¹⁴² or —SO₂R¹⁴³, R¹⁴¹-R¹⁴³ are eachindependently 1) C1-8 alkyl, 2) C2-8 alkenyl, 3) C2-8 alkynyl, 4) Cyc4or 5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4,R¹⁴⁸-R¹⁵⁰ are each independently 1) hydrogen, 2) C1-8 alkyl, 3) C2-8alkenyl, 4) C2-8 alkynyl, 5) Cyc4 or 6) C1-8 alkyl, C2-8 alkenyl or C2-8alkynyl substituted by Cyc4, Cyc4 has the same meaning as Cyc1, whereinCyc4 may be substituted by 1-5 of R¹⁴⁴, and R¹⁴⁴ has the same meaning asR⁵¹, R³ and R⁴, taken together, are

wherein R¹⁹⁰ and R¹⁹¹ each independently has the same meaning as R³ orR⁴, R⁵ is (1) hydrogen, (2) C1-8 alkyl, (3) Cyc5 or (4) C1-8 alkylsubstituted by Cyc5, wherein Cyc5 has the same meaning as Cyc1, and Cyc5may be substituted by 1-5 of R¹⁶⁰, R¹⁶⁰ has the same meaning as R⁵¹, aquaternary ammonium salt thereof, an N-oxide thereof, or a non-toxicsalt thereof.
 2. The method according to claim 1, wherein the disease isAIDS.
 3. The method according to claim 1, wherein said disease is HIVinfection acquiring multidrug resistance.
 4. The method according toclaim 1, wherein the triazaspiro[5.5]undecane compound represented byformula (I), a quaternary ammonium salt thereof, an N-oxide thereof, ora non-toxic salt thereof is administered with at least one additionalHIV infection treating agent.
 5. The method according to claim 2,wherein the triazaspiro[5.5]undecane compound represented by formula(I), a quaternary ammonium salt thereof, an N-oxide thereof, or anon-toxic salt thereof is administered with at least one additional HIVinfection treating agent.
 6. The method according to claim 3, whereinthe triazaspiro[5.5]undecane compound represented by formula (I), aquaternary ammonium salt thereof, an N-oxide thereof, or a non-toxicsalt thereof is administered with at least one additional HIV infectiontreating agent.
 7. The method according to any one of claims 4, 5 and 6,wherein said at least one additional HIV infection treating agent is aprotease inhibitor, a reverse transcriptase inhibitor, a fusioninhibitor or a chemokine regulator.